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{ "abstract": "Secondary lymphohistiocytosis is a severe inflammatory condition characterized by uncontrolled inflammatory response hyperactivation of antigen-presenting cells, hemophagocytosis, cytopenias, and multiorgan failure, and is secondary to subjacent pathologies such as cancer, infection, or immune disease. Standard treatment includes chemotherapy; however, this is not always possible or safe. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor can reduce inflammation and cytokine activity and has been used in refractory cases and first-line treatment. Here, we present a 35-year-old patient with HIV infection and secondary lymphohistiocytosis due to CMV/EBV infection who was successfully treated with ruxolitinib as first-line therapy. He rapidly showed clinical and biochemical improvement and transfusion independence without complications.", "affiliations": "Hospital General de Tijuana, Secretaría de Salud de Baja California, Avenida Centenario 10851, Zona Río, CP 22680, Tijuana, Baja California, Mexico. [email protected].;Hospital General Regional 20, Instituto Mexicano del Seguro Social, Boulevard Díaz Ordaz y Lázaro Cárdenas, La Meza, CP 22450, Tijuana, Baja California, Mexico.", "authors": "Gálvez Acosta\|Sergio\|S\|;Javalera Rincón\|Mariana\|M\|", "chemical_list": "D016207:Cytokines; D018836:Inflammation Mediators; D000075242:Janus Kinase Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib", "country": "Japan", "delete": false, "doi": "10.1007/s12185-020-02882-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "112(3)", "journal": "International journal of hematology", "keywords": "CMV/EBV infection; HIV infection; Ruxolitinib; Secondary hemophagocytic lymphohistiocytosis", "medline_ta": "Int J Hematol", "mesh_terms": "D000328:Adult; D016207:Cytokines; D003586:Cytomegalovirus Infections; D020031:Epstein-Barr Virus Infections; D015658:HIV Infections; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators; D000075242:Janus Kinase Inhibitors; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D016896:Treatment Outcome", "nlm_unique_id": "9111627", "other_id": null, "pages": "418-421", "pmc": null, "pmid": "32285358", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Ruxolitinib as first-line therapy in secondary hemophagocytic lymphohistiocytosis and HIV infection.", "title_normalized": "ruxolitinib as first line therapy in secondary hemophagocytic lymphohistiocytosis and hiv infection" }	[ { "companynumb": "NVSC2020MX141725", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "013422", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypophagia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cachexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serum ferritin increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhagic ascites", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemophagocytic lymphohistiocytosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GALVEZ AS, JAVALERA RM,. RUXOLITINIB AS FIRST-LINE THERAPY IN SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND HIV INFECTION. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2020", "literaturereference_normalized": "ruxolitinib as first line therapy in secondary hemophagocytic lymphohistiocytosis and hiv infection", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20200527", "receivedate": "20200527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17827993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]
{ "abstract": "Abnormalities of the upper airway anatomy are an underrecognized cause of obstructive sleep apnea. We present a unique case of a 51-year-old man with episodic sleep-maintenance insomnia and oromandibular dystonia requiring botulinum toxin injections of the temporalis and masseter muscles. He underwent multiple sleep studies and was found to have obstructive sleep apnea temporally associated with the severity of dystonia symptoms and dosing of botulinum toxin.", "affiliations": "Scripps Health, San Diego, California.;VA Greater Los Angeles Healthcare, Los Angeles, California.;VA Greater Los Angeles Healthcare, Los Angeles, California.;VA Greater Los Angeles Healthcare, Los Angeles, California.", "authors": "Hsu\|Nancy\|N\|;Hsieh\|Caleb\|C\|;Thomas\|Aaron\|A\|;Chang\|Melisa\|M\|", "chemical_list": "D001905:Botulinum Toxins", "country": "United States", "delete": false, "doi": "10.5664/jcsm.8454", "fulltext": null, "fulltext_license": null, "issn_linking": "1550-9389", "issue": "16(7)", "journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine", "keywords": "botulinum toxin; dystonic disorders; insomnia; obstructive sleep apnea", "medline_ta": "J Clin Sleep Med", "mesh_terms": "D001905:Botulinum Toxins; D004421:Dystonia; D006801:Humans; D008297:Male; D008875:Middle Aged; D017286:Polysomnography; D020181:Sleep Apnea, Obstructive", "nlm_unique_id": "101231977", "other_id": null, "pages": "1209-1212", "pmc": null, "pmid": "32248896", "pubdate": "2020-07-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "17882462;11966340;30604200;26866500;18250211;21992649;23666585;19960649;1643688;17503232", "title": "Obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin.", "title_normalized": "obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin" }	[ { "companynumb": "US-MERZ PHARMACEUTICALS GMBH-20-01497", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BOTULINUM TOXIN TYPE A" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125360", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OROMANDIBULAR DYSTONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOTULINUM TOXIN TYPE A" } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HSU N, HSIEH C, THOMAS A, CHANG M. OBSTRUCTIVE SLEEP APNEA DUE TO OROMANDIBULAR DYSTONIA AND TREATED WITH BOTULINUM TOXIN. J CLIN SLEEP MED. 2020?.", "literaturereference_normalized": "obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200710", "receivedate": "20200710", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18010838, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "BACKGROUND\nAmlodipine is a racemic mixture of (R)- and (S)-enantiomers. It has been suggested that removing the therapeutically inactive (R)-enantiomer will reduce adverse events while preserving the agent's efficacy. Women experience more adverse effects from amlodipine.\n\n\nOBJECTIVE\nThis exploratory study compared the amount of pedal edema experienced by female Korean patients with mild to moderate hypertension when receiving S(-)-amlodipine nicotinate compared with amlodipine besylate.\n\n\nMETHODS\nThis study was a 12-week, multicenter, randomized, double-blind, active-controlled, Phase IV clinical trial. Female patients with mild to moderate hypertension were randomly assigned to receive either S(-)-amlodipine nicotinate 2.5 to 5 mg once daily or amlodipine besylate 5 to 10 mg once daily for 12 weeks. The primary objective was to compare the change in ankle-foot volume quantified by using a water displacement method after 12 weeks of therapy. The secondary objectives were to compare the changes in mean sitting systolic and diastolic blood pressures. Safety assessment included monitoring all laboratory tests, adverse events (AEs), serious AEs, and possible relation to the study medication.\n\n\nRESULTS\nOf the 38 patients enrolled, 17 patients in each group were eligible for final analysis. In the S(-)-amlodipine nicotinate group, the mean ankle-foot volume at baseline was 1056.91 (98.15) mL, and volume after 12 weeks of treatment was 1016.68 (158.37) mL, a decrease of 40.24 (110.05) mL. In the amlodipine besylate group, mean ankle-foot volume at baseline was 1037.56 (158.30) mL, and volume after treatment was 1067.59 (152.54) mL, an increase of 30.03 (69.59) mL. There was a significant difference in the change of ankle-foot volume between the 2 groups (-70.26 mL [95% CI, -134.60 to -5.94], P = 0.028). After 12 weeks, the mean changes in sitting systolic blood pressure from baseline were not significantly different between the 2 groups (-21.82 [8.76] vs -26.82 [11.89] mm Hg; P = 0.172). Changes in mean sitting diastolic blood pressure also were not significant (-14.71 [6.94] vs -10.88 [5.81] mm Hg; P = 0.091). One patient in each group had facial edema, and another patient in the amlodipine besylate group had facial flushing. Overall, there was no significant difference in drug-related AEs between the 2 groups (P = 0.999).\n\n\nCONCLUSIONS\nThese female Korean patients with hypertension taking S(-)-amlodipine nicotinate had less ankle edema, with no significant difference in BP-lowering efficacy, compared with those taking amlodipine besylate. S(-)-amlodipine nicotinate may be a suitable alternative for patients intolerant to amlodipine besylate. (Clinical Research Information Service: CRiS, KCT0000450).", "affiliations": "Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.", "authors": "Oh\|Gyu-Chul\|GC\|;Lee\|Hae-Young\|HY\|;Kang\|Hyun-Jae\|HJ\|;Zo\|Joo-Hee\|JH\|;Choi\|Dong-Ju\|DJ\|;Oh\|Byung-Hee\|BH\|", "chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; C519553:amlodipine nicotinate; D017311:Amlodipine; D009525:Niacin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0149-2918", "issue": "34(9)", "journal": "Clinical therapeutics", "keywords": null, "medline_ta": "Clin Ther", "mesh_terms": "D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D001794:Blood Pressure; D002121:Calcium Channel Blockers; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004487:Edema; D005260:Female; D005500:Follow-Up Studies; D005528:Foot; D006801:Humans; D006973:Hypertension; D008875:Middle Aged; D009525:Niacin; D056910:Republic of Korea; D013237:Stereoisomerism", "nlm_unique_id": "7706726", "other_id": null, "pages": "1940-7", "pmc": null, "pmid": "22925988", "pubdate": "2012-09", "publication_types": "D017429:Clinical Trial, Phase IV; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Quantification of pedal edema during treatment with S(-)-amlodipine nicotinate versus amlodipine besylate in female Korean patients with mild to moderate hypertension: a 12-week, multicenter, randomized, double-blind, active-controlled, phase IV clinical trial.", "title_normalized": "quantification of pedal edema during treatment with s amlodipine nicotinate versus amlodipine besylate in female korean patients with mild to moderate hypertension a 12 week multicenter randomized double blind active controlled phase iv clinical trial" }	[ { "companynumb": "KR-ALKEM LABORATORIES LIMITED-KR-ALKEM-2022-01991", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078925", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 TO 10 MG ONCE DAILY FOR 12 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Oh GC, Lee HY, Kang HJ, Zo JH, et al. Quantification of pedal edema during treatment with S(-)-amlodipine nicotinate versus amlodipine besylate in female Korean patients with mild to moderate hypertension: a 12-week, multicenter, randomized, double-blind, active-controlled, phase IV clinical trial. Clin Ther. 2012;34(9):1940-7", "literaturereference_normalized": "quantification of pedal edema during treatment with s amlodipine nicotinate versus amlodipine besylate in female korean patients with mild to moderate hypertension a 12 week multicenter randomized double blind active controlled phase iv clinical trial", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20220623", "receivedate": "20220623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20997364, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "Breast cancer patients treated with adjuvant chemotherapy regimens containing alkylating agents and anthracyclines are at an increased risk for secondary myeloid malignancies, either acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Complex genomic changes (karyotypes and/or gene amplification) accompany the development of the secondary neoplasms. Here we present a unique case of a breast cancer patient who developed secondary AML within 18 months of treatment with trastuzumab, pertuzumab, docetaxel, carboplatin (TCHP) and radiation. Leukemia cells had catastrophic alterations in chromosomes 8, 11, and 17. Genetic abnormalities in the leukemia cells included amplification of MYC and KMT2A as double minutes, and deletion and mutational inactivation of TP53 Concurrent amplification of different genes at different levels and on different double minutes, we have named \"double minute heterogeneity.\" Clinically, this case highlights the need to identify genes amplified in secondary myeloid malignancies by cytogenomic microarray (CMA) analysis since these may have therapeutic implications.", "affiliations": "Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA. Electronic address: [email protected].;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.", "authors": "Koduru\|Prasad\|P\|;Chen\|Weina\|W\|;Haley\|Barbara\|B\|;Ho\|Kevin\|K\|;Oliver\|Dwight\|D\|;Wilson\|Kathleen\|K\|", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": "10.1016/j.cancergen.2019.08.001", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "238()", "journal": "Cancer genetics", "keywords": "Amplification; Breast cancer; Double minutes; KMT2A; MYC; Secondary AML", "medline_ta": "Cancer Genet", "mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged; D016609:Neoplasms, Second Primary", "nlm_unique_id": "101539150", "other_id": null, "pages": "69-75", "pmc": null, "pmid": "31425928", "pubdate": "2019-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia.", "title_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia" }	[ { "companynumb": "US-PFIZER INC-2019382758", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "022234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC (6 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201701" } }, "primarysource": { "literaturereference": "KODURU, P.. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA.. 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CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16806759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-SA-2019SA236573", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, 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"reaction": [ { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pallor", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Granulocytes abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Petechiae", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Chromosomal mutation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myeloblast percentage increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K.. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190906", "receivedate": "20190827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16748039, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-MYLANLABS-2019M1084594", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077998", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER-GENET 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16809552, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "US-DRREDDYS-USA/USA/19/0113873", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204193", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chromosomal mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75. DOI: 10.1016/J.CANCERGEN.2019.08.001.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191016", "receivedate": "20190904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16770732, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-FRESENIUS KABI-FK201909919", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16806780, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-220754", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77926", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENET. 2019?238:69?75", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20190918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16821135, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" }, { "companynumb": "US-ACCORD-153452", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "206775", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "201195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chromosomal mutation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201701" } }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENET. 2019 AUG 6?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16783481, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-TEVA-2019-US-1108673", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYUREA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYUREA." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "77269", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUMOUR LYSIS SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203551", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACOGEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RASBURICASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUMOUR LYSIS SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RASBURICASE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER-GENET 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190927", "receivedate": "20190917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16818621, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" } ]
{ "abstract": "Background: Epstein-Barr virus (EBV) infection is associated with significant morbidity and mortality in renal transplant (RT) recipients. The spectrum of illness ranges from infectious mononucleosis (IM) to post-transplant lymphoproliferative disorder (PTLD). In association with clinical signs and symptoms, virus-specific serology and heterophile antibody tests are widely used in confirming the diagnosis of IM in the general population. However, these tests may have a limited role in immunosuppressed RT recipients from seropositive donor, especially in children who were EBV-seronegative prior to the transplant. The aim of this study is to evaluate the utility of these tests in the early diagnosis of IM in this subset of patients. Methods: This is a case study with a review of literature. Results: Here, we present a 14-year-old male with hemophilia B who presented with fever, fatigue, sore throat, palatal petechial rash, exudative tonsillitis and cervical lymphadenopathy 3 months post-RT. He was EBV seronegative prior to RT and received a deceased donor kidney transplant from a seropositive donor. Induction was done with Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. Initial heterophile antibody test (monospot) was negative, but became positive at 5 months and remained positive at 9 months follow-up post-RT. EBV viral capsid antigens (VCA) IgM and IgG, early antigen (EA) and nuclear antigen (EBNA) were all negative at the time of presentation. VCA IgM and IgG both became positive at 5 months and peaked at 9 months follow-up, however the EA and EBNA remained negative. EBV viral load as measured by polymerase chain reaction (PCR) was negative for the first 3 months post-RT but became positive at presentation, peaked at 6 months and started declining thereafter. Peripheral blood smear examination showed no absolute and atypical lymphocytosis. Cytomegalovirus PCR in the blood and throat culture for streptococcus were negative. There was no splenomegaly. He was managed conservatively with intravenous fluids, bed rest, antipyretics and reduction of immunosuppression. Conclusions: EBV serological markers have a limited role in the early diagnosis of EBV-IM following RT in prior seronegative children. Initial heterophile antibody test may also be negative, and hence a repeat test may be necessary. Once becoming positive, the VCA IgM may remain persistently elevated for prolonged duration. In addition to the suppressed cellular immunity secondary to immunosuppression, humoral response to viral infections is also delayed in transplant recipients, especially in the early transplant period. Hence, routine monitoring with PCR is superior to serology in diagnosing IM early and monitoring the EBV infection post-RT for timely evaluation and management.", "affiliations": "Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.;Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.;Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.;Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.", "authors": "Byrne\|Alexandra\|A\|;Bush\|Rachel\|R\|;Johns\|Felicia\|F\|;Upadhyay\|Kiran\|K\|0000-0002-8441-0220", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/medicines7040021", "fulltext": "\n==== Front\nMedicines (Basel)\nMedicines (Basel)\nmedicines\nMedicines\n2305-6320 MDPI \n\n10.3390/medicines7040021\nmedicines-07-00021\nCase Report\nLimited Utility of Serology and Heterophile Test in the Early Diagnosis of Epstein–Barr Virus Mononucleosis in a Child after Renal Transplantation\nByrne Alexandra 1 Bush Rachel 2 Johns Felicia 2 https://orcid.org/0000-0002-8441-0220Upadhyay Kiran 2* 1 Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA\n2 Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA\n* Correspondence: [email protected]; Tel.: +352-273-9180\n22 4 2020 \n4 2020 \n7 4 2102 4 2020 20 4 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Epstein–Barr virus (EBV) infection is associated with significant morbidity and mortality in renal transplant (RT) recipients. The spectrum of illness ranges from infectious mononucleosis (IM) to post-transplant lymphoproliferative disorder (PTLD). In association with clinical signs and symptoms, virus-specific serology and heterophile antibody tests are widely used in confirming the diagnosis of IM in the general population. However, these tests may have a limited role in immunosuppressed RT recipients from seropositive donor, especially in children who were EBV-seronegative prior to the transplant. The aim of this study is to evaluate the utility of these tests in the early diagnosis of IM in this subset of patients. Methods: This is a case study with a review of literature. Results: Here, we present a 14-year-old male with hemophilia B who presented with fever, fatigue, sore throat, palatal petechial rash, exudative tonsillitis and cervical lymphadenopathy 3 months post-RT. He was EBV seronegative prior to RT and received a deceased donor kidney transplant from a seropositive donor. Induction was done with Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. Initial heterophile antibody test (monospot) was negative, but became positive at 5 months and remained positive at 9 months follow-up post-RT. EBV viral capsid antigens (VCA) IgM and IgG, early antigen (EA) and nuclear antigen (EBNA) were all negative at the time of presentation. VCA IgM and IgG both became positive at 5 months and peaked at 9 months follow-up, however the EA and EBNA remained negative. EBV viral load as measured by polymerase chain reaction (PCR) was negative for the first 3 months post-RT but became positive at presentation, peaked at 6 months and started declining thereafter. Peripheral blood smear examination showed no absolute and atypical lymphocytosis. Cytomegalovirus PCR in the blood and throat culture for streptococcus were negative. There was no splenomegaly. He was managed conservatively with intravenous fluids, bed rest, antipyretics and reduction of immunosuppression. Conclusions: EBV serological markers have a limited role in the early diagnosis of EBV-IM following RT in prior seronegative children. Initial heterophile antibody test may also be negative, and hence a repeat test may be necessary. Once becoming positive, the VCA IgM may remain persistently elevated for prolonged duration. In addition to the suppressed cellular immunity secondary to immunosuppression, humoral response to viral infections is also delayed in transplant recipients, especially in the early transplant period. Hence, routine monitoring with PCR is superior to serology in diagnosing IM early and monitoring the EBV infection post-RT for timely evaluation and management.\n\nEpstein–Barr virusserologymononucleosisrenal transplantpediatric\n==== Body\n1. Introduction\nEpstein–Barr virus (EBV), a double-stranded, enveloped DNA virus, belonging to the gamma herpes virus family, is the most common cause of infectious mononucleosis (IM). EBV infects over 90% of the human population worldwide and the rates of infection are higher among ages 15–24 years with 6–8 cases/1000 persons per year [1]. By four years of age, EBV seroprevalence is close to 100% in developing countries and 25–50% in lower socioeconomic groups in the United States [2]. IM is characterized by a triad of fever, tonsillar pharyngitis, and cervical lymphadenopathy [3]. The primary modes of exposure are saliva, organ transplantation or blood transfusion [4,5]. EBV-associated IM is a benign lymphoproliferative disorder in most immunocompetent patients, but may cause significant morbidity and mortality in those who are immunosuppressed, including renal transplant (RT) recipients [6,7]. EBV predominantly infects the epithelial and B cells. In RT recipients, the decreased anti-EBV T-cell immune surveillance, due to usage of immunosuppressive agents, may allow aberrant outgrowth of EBV-transformed B-cells leading to malignant post-transplant lymphoproliferative disorders (PTLD) [8,9,10]. The risk for developing PTLD is especially higher in pre-transplant EBV seronegative recipients, which is true for most young children. The incidence rate of PTLD is 4–22% for the various categories of pediatric organ transplant recipients as opposed to an average of 1–2% in adults [11].\n\nSimilar to the non-immunosuppressed patients, the presumptive diagnosis of EBV-associated IM in immunosuppressed RT recipients can be made clinically. However, a definite diagnosis does require demonstration of positive EBV serology and/or heterophile test since IM-like clinical picture can be seen with cytomegalovirus (CMV), human immunodeficiency virus (HIV) and Group A streptococcal infections [12,13], among others. The virus-specific serology poses a challenge, especially in prior seronegative children, due to delayed or absent humoral response [14]. In addition, heterophile tests (monospot) tests are less sensitive early in the course of illness and in young children [15,16]. Hence, relying on these tests only may cause a delay in diagnosis. Quantitative polymerase chain reaction (PCR) to detect EBV DNA in whole blood or serum is used to monitor EBV infection in the RT recipients [17]. Since PCR is independent of the body’s ability to mount cellular or humoral immunity, it can be a more reliable test to confirm EBV mononucleosis in the presence of clinical signs and symptoms. Here, we present a 14-year-old EBV-seronegative adolescent who presented with typical clinical features of IM, negative serology and monospot test, but with positive PCR, three months after RT from a seropositive donor.\n\n2. Methodology\nHeterophile antibody test was performed by both solid phase immunoassay and by latex agglutination assay. Antibodies to viral capsid antigen (VCA) IgM and IgG, early and nuclear antigens, were performed by semi-quantitative chemiluminescent immunoassay. EBV viral load was measured by quantitative PCR.\n\n3. Case Presentation\nA 14-year-old Caucasian male with hemophilia B underwent a deceased donor RT for end stage renal disease secondary to ischemic renal injury from intra-abdominal bleeding at birth. Chronic nightly peritoneal dialysis was initiated five months prior to the transplant. Treatment for hemophilia B included factor IX replacement therapy. He did not require blood transfusions due to the neonatal period. He had received all routine immunizations prior to the transplant. Induction was done with a total of 4.5 mg/kg of Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. He was on a steroid withdrawal protocol. There was an EBV mismatch between the donor and recipient (donor positive and recipient negative for EBV immunoglobulin (Ig) G). His serum EBV VCA IgG was 10.5 IU/mL (not detected: 17.9 U/mL or less) at the time of transplant. Both donor and recipient were CMV IgG positive. He had an immediate recovery of renal function post-RT with baseline serum creatinine of 0.9–1 mg/dL. Monthly viral surveillances for EBV, CMV and BK virus post-RT showed absence of viremia by PCR. Three months post–RT, he presented with fever, sore throat, and fatigue. His immunosuppression regimen at that time included tacrolimus 1.5 mg twice daily and mycophenolate 500 mg twice daily. Serum trough tacrolimus levels were at therapeutic level, as per our institution’s protocol. Anti-infective prophylaxis consisted of sulfamethoxazole-trimethoprim 800–160 mg three times weekly, and valganciclovir 450 mg daily. He had completed a 6-week course of prophylactic nystatin post-RT. Treatment of hemophilia B continued with once weekly factor IX infusions. There were no household sick contacts and he denied oral contact with another person. He had no other post-operative complications or acute rejection and reported adherence to the medications. \n\nTen days prior to this presentation, the patient had developed a sore throat and fatigue for a week. Both the rapid streptococcal and heterophile antibody test by latex agglutination were negative at that time. Supportive measures for viral pharyngitis were done; however, over the next 10 days, his symptoms progressed with the development of fever, prompting this presentation. \n\nOn examination, his vital signs were as follows: temperature 101.1 ⁰F, pulse 100 beats per minute, respiratory rate 18 per minute, oxygen saturation 99% on room air, and blood pressure 130/80 mm Hg. Height and weight were both at 50th centile. He was ill-appearing and was sitting in a tripod position. Throat and neck examination showed significant bilateral tonsillar enlargement, erythema, and exudate (Figure 1) and tender anterior cervical lymphadenopathy. Abdominal examination showed no tenderness to palpation over his transplanted kidney in his right lower quadrant and an absence of splenomegaly. Investigations revealed elevated serum C-reactive protein of 40 mg/L (0–5 mg/L), white blood cell count of 3.4 × 103/mm3, absolute neutrophil and lymphocyte count of 2800 cells/µL and 240 cells/µL, respectively, and atypical lymphocytes of 1%. Hemoglobin, platelet count and liver function test were all in normal range. Renal function test showed serum creatinine of 1.2 mg/dL (baseline 0.9–1 mg/dL) with stable electrolytes. Given EBV discordance (donor EBV + and recipient EBV −) along with fever, exudative tonsillitis, cervical lymphadenopathy and fever, there was a high index of suspicion for IM secondary to EBV. However, the heterophile antibody test by both solid phase immunoassay and latex agglutination assays was negative again. Furthermore, the serologic tests were all negative (EBV VCA IgM < 10 U/mL (not detected: 0–43.9 IU/mL), VCA IgG 15 IU/mL (not detected: 0–17.9 IU/mL), early antigen (EA) IgG < 5 IU/mL (not detected: 0–8.9 IU/mL), nuclear antigen (EBNA) IgG < 3 IU/mL (not detected: 0–17.9 IU/mL)). Serum CMV PCR and BK virus PCRs were negative. Whole blood EBV quantitative PCR showed EBV viral load of 1970 copies/mL. (undetectable: <390 copies/mL; ARUP laboratories, Salt lake City, UT, USA). Prior EBV PCR loads were undetectable at one and two month post-RT follow-up appointments. Bartonella henselae, Bartonella quintana, Toxoplasma gondii IgG and IgM antibodies along with serum adenovirus PCR were all negative. Serum tacrolimus trough level was at goal (6–7 ng/mL, as per our institution’s protocol). Hepatitis screen, HIV, antinuclear antibody, and rheumatoid factor were negative. Peripheral blood smear did not show evidence of blast cells. Abdominal sonogram showed normal appearing renal transplant with no splenomegaly. Throat culture was negative for beta-hemolytic streptococcus, corynebacterium diphtheriae, fungus, chlamydia and gonorrhea. Nasopharyngeal swab test for influenza and other respiratory viruses were negative. Due to tripod position on examination, X-ray along with computed tomography scan of the neck without contrast were done which showed narrowing of the airway due to soft tissue swelling but without any peritonsillar or retropharyngeal abscess. However, his respiratory status remained stable on room air throughout without the need for supplemental oxygen therapy. Steroid therapy was not required. He also developed acute hemoptysis, most likely secondary to tonsillar friability in the setting of low factor IX levels, prompting administration of an additional dose of factor IX with resolution of hemoptysis. He was treated with acetaminophen, intravenous fluid therapy and 3rd generation cephalosporin, the latter was discontinued after the throat and blood bacterial cultures resulted negative. Mycophenolate dose was decreased to 250 mg twice daily. He was discharged to home on sixth day of admission once he became afebrile and adequate oral intake was ensured. Discharge medications consisted of tacrolimus, mycophenolate, valganciclovir, TMP-SMX and factor IX replacement therapy. \n\nAt subsequent outpatient clinic follow-up visits, whole blood EBV PCR showed a persistent rise to a peak level of 10,200 copies/mL at 6 months, and then gradual decline to 2460 copies/mL at 9 months post-RT (Figure 2). VCA IgM and IgG both became positive at 5 months and subsequently peaked at his most recent 9-month follow-up (Figure 2). Monospot test (latex agglutination) also became positive at 5 months and remained positive at the 9 month post-RT follow-up. Clinical examination showed persistent mild sore throat, tonsillar enlargement and cervical lymphadenopathy until about 5 months when the symptoms started resolving. At his most recent 9-month follow-up visit, he was asymptomatic with resolution of tonsillar enlargement and cervical lymphadenopathy. Renal allograft function remained stable. Serum CMV and BK virus PCRs remained negative. \n\n4. Discussion\nEBV infection in transplant recipients may be a primary infection or a reactivation of a prior latent infection [8,18]. Primary infection occurs mainly via exchange of saliva or sharing household items from close-contacts, transplantation of kidney from a seropositive donor in a seronegative recipient or through blood transfusions [19,20]. Reactivation occurs in those with latent EBV and then undergo active viral multiplication in the setting of immunosuppression post–RT. The serologic diagnosis of reactivation/reinfection requires a 10-fold increase in anti-VCA IgG or the presence of anti-VCA IgM in previously IgG seropositive patients [21]. Our patient did not have a history of saliva exchange, sick contacts, and blood transfusions; hence he most likely had a primary infection through the transplantation from the seropositive donor. A single center study of pediatric solid organ transplant (SOT) recipients showed that the seroconversion rate in prior seronegative pediatric liver transplant patients was >75% while reactivation occurred in 50% of prior seropositive recipients [22]. Patients with primary infection had more viral shedding than those who were seropositive at the time of transplant, and heart transplant recipients had higher levels of peak shedding than renal allograft recipients [23]. In terms of risk factor for development of PTLD, primary EBV infection has been shown to be much more of a risk than reactivated infection [24]. Ho et al. described 11 children with EBV-associated lymphoproliferative syndrome post-SOT and 10 had a primary infection. These children were at greater risk due to them being seronegative for EBV prior to the transplant who then acquired primary infection with the transplant from seropositive donor [22]. Other studies have similarly shown that recipients who are seronegative at the time of transplant are more likely to be symptomatic and have EBV related complications, such as PTLD [6,7,25]. \n\nThe most commonly used tests to diagnose EBV-associated IM include heterophile test, serology and PCR. Paul–Bunnell test, the original heterophile antibody test, utilized sheep red blood cells (RBC) while most of the currently used heterophile antibody or the Monospot tests use horse RBCs with improvement in the test if these RBCs were first absorbed to guinea pig kidney or bovine RBCs before sera were added [26]. In immunocompetent patients, initially, the B cells produce polyclonal antibodies in response to EBV infection which are directed against viral and unrelated antigens found on sheep and horse RBCs. The antibodies against the latter antigens, termed heterophile antibodies, comprise only about 5% of total polyclonal antibodies [27]. They are mostly IgM antibodies that do not cross-react with EBV antigens and are the basis of heterophile antibody test [28,29]. Later in the course of EBV infection, these B cells are kept in check by the recruitment of cytotoxic CD8+ T cells which provide a polyclonal regulatory response, and are an important part of host defense mechanism against EBV [30]. Since the peak levels of virus-specific IgM and IgG response usually occurs only around 6–17 days after the onset of clinical symptoms, the serology may not be helpful in the early stage of presentation [31]. The incubation period of IM is usually 2–7 weeks and since the heterophile antibodies are seen 2–9 weeks after the person is infected, heterophile antibody tests may be preferable for early diagnosis at the time of presentation. Commercial test kits for these antibodies (by solid phase immunoassay or latex agglutination assay) are available and have sensitivities of 70–92% and a specificity of 96–100%, with a lower sensitivity in the first two weeks of illness [32]. The false negativity rate of these tests could be as high as 25% in the first week, 5–10% in the second week, and 5% in the third week [15]. Latex-based heterophile antibody assays may be a little more sensitive than the solid phase assays but the specificity is similar between the two [33]. Our patient was tested with both solid phase and latex agglutination assays. In addition, in younger patients less than 12 years of age, the test sensitivity is only 25–50%, as compared to 71–91% in older patients [15]. Horwitz et al. showed that children 1–2 years of age were significantly less likely to have positive heterophile antibody tests compared with children 2–4 years of age (27.3% vs. 76.2%) [16]. Therefore, heterophile tests may only be appropriate for use in older children. Once formed, these antibodies disappear in few weeks but in some, they may persist for up to a year after infection [28]. Hence, heterophile antibody tests may help diagnose IM retrospectively in some patients, if the initial test was negative, as in our case. Moreover, the antibodies detected by the test can be caused by conditions other than IM (for example, CMV, hepatitis, rubella, HIV, autoimmune conditions, adenovirus) due to cross reactivity with these conditions [32]. Our patient had negative CMV and adenovirus PCRs along with negative hepatitis and HIV tests. Due to these limitations, Center for Disease Control and Prevention in Unites States does not recommend the heterophile test for general use in the diagnosis of IM, instead suggesting viral serology as a method of choice [34]. \n\nThe initial serologic response to EBV infection occurs with the production of IgM antibody to the VCA in about 75% of patients [35], which usually disappears within 4–6 weeks. In immunosuppressed patients, however, the viral shedding may be prolonged, symptoms may last longer and be more severe [36]. Hence, once the intense immunosuppression period of T lymphocyte depletion is over (usually few months post-transplant), in the setting of persistent viral shedding, the newly produced host T cells will continue to stimulate B cells to produce virus-specific IgM and IgG. This could have led to the delayed onset but more prolonged presence of IgM antibody in our patient. Anti-VCA IgG also appears in the acute phase of EBV infection, peaks at 2–4 weeks after onset in most patients, declines slightly and then persists for the rest of a person’s life. Hence, the presence of VCA IgG indicates that the infection has occurred in the past. Antibody to early antigen (EA) is present in 60–80% only, and may indicate active viral replication and is especially helpful if the heterophile antibody is negative and VCA IgG or IgM yields inconclusive results. Of note, 20% of healthy individuals can have EBV EA antigen [35]. Anti-EA IgG generally falls to undetectable levels after 3–6 months. Antibody to nuclear antigen (EBNA) is not seen in the acute phase but slowly appears 2–4 months after the onset of symptoms and persists for the rest of a person’s life [37]. The infection then remains latent. Hence, the comparison of paired sera from acute and convalescent period showing presence of EBNA IgG in the absence of VCA IgM rules out the acute infection. With regards to the efficacy of serology, Bruu et al. analyzed six commercial tests for EBV-specific antibodies, with sensitivities ranging from 95–100% and specificities ranging from 86–100% [38]. Hence, EBV-specific serology appears to be more sensitive but less specific than heterophile antibody testing. The reduced specificity is due to significant cross-reactivity of VCA-IgM to other infections such as CMV [38]. On the other hand, increased sensitivity of serology, including IgM, can produce false positive results [39].\n\nSimilar to the delayed serological response after immunization in SOT recipients [40], serology unfortunately is unreliable as a diagnostic test for either PTLD or primary EBV infection in transplant recipients [8]. These patients show a marked delay in their humoral response to EBV antigens, and many fail to develop IgM antibodies altogether [8,14,41]. Both T and B cells are required to induce an antibody response. T follicular helper cells provide seven main forms of T cell help to B cells: signals that promote survival, proliferation, plasma cell differentiation, hypermutation, class-switch recombination, adhesion and chemo-attraction (cell migration) [42]. Hence, in the absence of cytotoxic T cells secondary to usage of lymphocyte-depleting immunosuppressive agents, the humoral response is also inhibited along with cellular immunity [42]. This state of T cell anergy allows EBV to escape the immune elimination by utilizing a distinct latency expression programs to establish a persistent infection and potentially leading to PTLD [30,43]. It is important to remember that T cell anergy can also occur due to T cell receptor-specific impairment in the induction of genes involved in T cell proliferation, allowing uninhibited proliferation of infected B cells, in some immunocompetent patients with acute IM [44]. Regardless of the mechanism of anergy, the antibody response is reduced and in some cases may be selective. Diminished or absent antibody response to EBNA may be observed despite persistence of anti VCA IgG. Cen et al. described a markedly reduced antibody response to the latent cycle antigens, EBNA 1, EBNA 2 and EBNA-LP in immunosuppressed SOT recipients with PTLD, but not to the lytic cycle VCA when compared to the normal immunocompetent controls [45]. At 9-month follow-up, our patient had not been able to produce anti-EBNA IgG although the VCA IgG had reached its peak level. Hence, the typical pattern of appearance of serological markers may not be evident in these patients. \n\nEBV PCR measures the quantitative viral load in the blood and is the most sensitive test for detecting EBV infection in the post-transplant period [17]. A variety of blood specimens have been used for EBV load quantification, including unfractionated whole blood, peripheral blood mononuclear cells, and plasma. However, the whole blood EBV DNA is believed to be superior to plasma EBV DNA as the cell-associated EBV can be detected well before the plasma DNA is detected. Additionally, the cell DNA may be present at high levels without even being present in the plasma [21,46]. The whole blood sample is also simple to process and provides quantification of both cell-associated and cell-free virus, yielding an absolute viral load, irrespective of concerns about fluctuations in cell number, lysis and loss during separation [17]. Hence, transplant clinical guidelines suggest monitoring of high-risk patients for EBV-related PTLD by nucleic acid testing post-RT instead of serology [47]. In a large, retrospective study of the incidence of PTLD in RT recipients in the United States, the risk of PTLD was more than six times higher for donor+/recipient- deceased donor transplants compared with R+ transplants [48]. However, there are no clinical guidelines that exist for diagnosis of EBV-IM without PTLD in the post-RT period. Since the EBV serology and heterophile tests may be negative in the early post-RT period, this report emphasizes the value of repeat testing of serology and heterophile tests to establish a diagnosis of IM. It is important to know that since low level detection of EBV by PCR is common in transplant recipients [49], the mere presence of a positive viral load does not always indicate mononucleosis in the absence of the classic presentation such as lymphadenopathy, pharyngitis and fever. Hence, the serial testing of serology and heterophile tests may have a role in retrospectively establishing a diagnosis of IM in these patients. \n\nOther tests that may be useful in diagnosis of IM are lymphocyte to white cell count ratio, real-time PCR targeting various EBV genes, an absolute increase in the number of peripheral lymphocytes, and atypical lymphocytes [50,51,52]. Studies on lymphocyte to white cell count ratio as a diagnostic marker of IM has shown conflicting results [50]. Usage of raised absolute lymphocyte count has been suggested as providing a quick clue to the diagnosis of IM while awaiting for serology or heterophile antibody test result [52]. The atypical lymphocytes are primary T cells, produced in response to the EBV-infected B cells [29]. Commonly, absolute lymphocytosis (>50% lymphocytes) in the presence of >10% atypical lymphocytes are considered diagnostic of IM. The case presented in this report did not have absolute lymphocytosis with only 1% atypical lymphocytes, most likely secondary to lymphopenia from immunosuppression. Hence, lymphocyte-based assays are unlikely to be useful in transplant recipients, especially in the early post-transplant period. \n\n5. Conclusions\nThe EBV serology may underestimate the active presence of EBV in seronegative SOT recipients. Furthermore, in the absence of positive heterophile antibodies, the confirmatory diagnosis of mononucleosis becomes much more difficult. Not only has the EBV DNA load in the blood allowed risk assessment of development of EBV-associated disease in immunosuppressed patients, it also is helpful in making a definite diagnosis of IM in the presence of clinical signs and symptoms.\n\nAuthor Contributions\nA.B.: Collected data and prepared the original draft; R.B., F.J.: Collected data and prepared the original draft, and critically reviewed and revised the manuscript. K.U.: Conceptualized the study, collected data and prepared the original draft, and critically reviewed and revised the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis study received no funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Oropharyngeal examination showing bilateral tonsillar enlargement with exudates.\n\nFigure 2 Timeline of Epstein–Barr virus (EBV) serology and polymerase chain reaction (PCR) post-renal transplantation. EBV serologies (viral capsid antigen (VCA) IgM, VCA IgG, early antigen (EA) and nuclear antigen (EBNA) IgG expressed in IU/mL) and EBV DNA PCR expressed in copies/mL.\n==== Refs\nReferences\n1. Fleisher G. Henle W. Henle G. Lennette E.T. Biggar R.J. Primary infection with Epstein-Barr virus in infants in the United States J. Infect. Dis. 1979 139 553 558 10.1093/infdis/139.5.553 220340 \n2. Gares V. Panico L. Castagne R. Delpierre C. Kelly-Irving M. 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Andiman W. Starzl T.E. Eastman R. Griffith B.P. Hardesty R.L. Epstein-Barr virus infections and DNA hybridization studies in posttransplantation lymphoma and lymphoproliferative lesions: The role of primary infection J. Infect. Dis. 1985 152 876 878 10.1093/infdis/152.5.876 2995512 \n25. Nijland M.L. Kersten M.J. Pals S.T. Bemelman F.J. Ten Berge I.J. Epstein-Barr Virus-positive posttransplant lymphoproliferative disease after solid organ transplantation: Pathogenesis, clinical manifestations, diagnosis, and management Transplant. Direct 2015 2 e48 10.1097/TXD.0000000000000557 27500242 \n26. Lee C.L. Zandrew F. Davidsohn I. Horse agglutinins in infectious mononucleosis: III criterion for differential diagnosis J. Clin. Pathol. 1968 21 631 634 10.1136/jcp.21.5.631 5697368 \n27. Wollheim F.A. Williams R.C. Jr. Studies on the macroglobulins of human serum- polyclonal immunoglobulin class M (IgM) increase in infectious mononucleosis N. Engl. J. 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Otolaryngol. 2011 36 515 516 10.1111/j.1749-4486.2011.02367.x 22032455\n\n", "fulltext_license": "CC BY", "issn_linking": "2305-6320", "issue": "7(4)", "journal": "Medicines (Basel, Switzerland)", "keywords": "Epstein–Barr virus; mononucleosis; pediatric; renal transplant; serology", "medline_ta": "Medicines (Basel)", "mesh_terms": null, "nlm_unique_id": "101671069", "other_id": null, "pages": null, "pmc": null, "pmid": "32331303", "pubdate": "2020-04-22", "publication_types": "D002363:Case Reports", "references": "9077426;25774295;23042966;18159378;18094380;1628427;6260269;10589949;25677493;29202893;27193039;4158937;8167350;1328412;4316146;30656214;11283064;2995512;8382973;1670959;3146367;28130396;19013244;6199144;7804700;10655355;220340;22032455;2828417;15508538;8555507;20860842;15541197;27500242;27016725;21108750;12153173;226884;5697368;1320711;23451126;19845597;14523386;25013625;23717200;10799460;11283029;10944566;2833828;22273720", "title": "Limited Utility of Serology and 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{ "abstract": "To investigate the efficacy of intravitreal injection of recombinant tissue plasminogen activator (rt-PA), ranibizumab, and gas without vitrectomy for submacular hemorrhage.\n\n\n\nProspective, interventional, consecutive case series.\n\n\n\nTwenty consecutive patients (20 eyes) with submacular hemorrhage secondary to exudative age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV).\n\n\n\nRanibizumab, rt-PA (25 μg/0.05 ml), and 100% perfluoropropane (0.3 ml) were injected intravitreally, followed by 2-day prone positioning.\n\n\n\nThe primary outcome measure was best-corrected visual acuity (BCVA) 6 months after treatment. Secondary outcome measures included central retinal thickness (CRT), central pigment epithelial detachment (PED) thickness, central ellipsoid zone, recurrence rate, and complications.\n\n\n\nUnderlying disease was exudative AMD in 1 eye and PCV in 19 eyes. Submacular hemorrhage ranged in size from 2 to 31 disc diameters. Complete displacement of submacular hemorrhage was achieved in 17 eyes (85%), and partial displacement was achieved in 3 eyes (15%). Snellen BCVA improved from 20/139 before treatment to 20/65 at 6 months (P = 0.0061). Mean change in Early Treatment Diabetic Retinopathy Study score from baseline was +13 letters (P = 0.0040). Mean CRT decreased from 599 μm before treatment to 208 μm at 6 months (P < 0.0001), and central PED thickness decreased from 188 to 88 μm (P = 0.0140). Three eyes developed vitreous hemorrhage, and 1 eye developed retinal detachment; all were treated surgically, and Snellen BCVA improved at 6 months (P = 0.0012). Recurrence was observed in 10 eyes (50%) within 6 months, but visual acuity was preserved with intravitreal injection of anti-vascular endothelial growth factor (VEGF) pro re nata (PRN). The factors that affect BCVA at 6 months after treatment were pre- and posttreatment central ellipsoid zone (P = 0.0366 and P = 0.0424), pretreatment BCVA (P = 0.0015), and pre- and posttreatment central PED thickness (P = 0.0046, P = 0.0021).\n\n\n\nSubretinal hemorrhage treatment by intravitreal injection of rt-PA, ranibizumab, and gas is useful to achieve hemorrhage displacement and lesion improvement. To preserve visual acuity, early detection of posttreatment recurrence and intravitreal anti-VEGF injection PRN are necessary.", "affiliations": "Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan. Electronic address: [email protected].;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.", "authors": "Kitagawa\|Yorihisa\|Y\|;Shimada\|Hiroyuki\|H\|;Mori\|Ryusaburo\|R\|;Tanaka\|Kouji\|K\|;Yuzawa\|Mitsuko\|M\|", "chemical_list": "D020533:Angiogenesis Inhibitors; D005343:Fibrinolytic Agents; D005466:Fluorocarbons; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C042852:perflutren; D010959:Tissue Plasminogen Activator; D000069579:Ranibizumab", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0161-6420", "issue": "123(6)", "journal": "Ophthalmology", "keywords": null, "medline_ta": "Ophthalmology", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D020256:Choroidal Neovascularization; D003131:Combined Modality Therapy; D058450:Endotamponade; D005260:Female; D005343:Fibrinolytic Agents; D005451:Fluorescein Angiography; D005466:Fluorocarbons; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D011127:Polyps; D016684:Prone Position; D011446:Prospective Studies; D000069579:Ranibizumab; D012166:Retinal Hemorrhage; D010959:Tissue Plasminogen Activator; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration", "nlm_unique_id": "7802443", "other_id": null, "pages": "1278-86", "pmc": null, "pmid": "26949121", "pubdate": "2016-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Intravitreal Tissue Plasminogen Activator, Ranibizumab, and Gas Injection for Submacular Hemorrhage in Polypoidal Choroidal Vasculopathy.", "title_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy" }	[ { "companynumb": "JP-ROCHE-1737206", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "012", "drugtreatmentduration": 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"drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125156", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYPOIDAL CHOROIDAL VASCULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERFLUTREN" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERFLUOROPROPANE" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitreous haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITAGAWA Y, SHIMADA H, MORI R, TANAKA K AND YUZUWA T. INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR, RANIBIZUMAB, AND GAS INJECTION FOR SUBMACULAR HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. OPHTHALMOLOGY 2015 NOV 06;:1-9.", "literaturereference_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160406", "receivedate": "20160406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12240690, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-ROCHE-1733784", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "125156", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERFLUTREN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYPOIDAL CHOROIDAL VASCULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERFLUOROPROPANE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125156", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYPOIDAL CHOROIDAL VASCULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POLYPOIDAL CHOROIDAL VASCULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERFLUTREN" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERFLUOROPROPANE" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Retinal detachment", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITAGAWA Y, SHIMADA H, MORI R, TANAKA K AND YUZUWA T. INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR, RANIBIZUMAB, AND GAS INJECTION FOR SUBMACULAR HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. OPHTHALMOLOGY 2015 NOV 06;:1-9.", "literaturereference_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160405", "receivedate": "20160405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12237643, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "OBJECTIVE\nThe objective of this study was to characterize chemotherapy treatment patterns in elderly patients with epithelial ovarian cancer (EOC) and their impact on overall survival (OS).\n\n\nMETHODS\nWe identified patients age ≥65years with stage II-IV EOC who underwent cytoreduction from 2003 to 2011. Relevant clinical variables were extracted and correlated with OS. Statistical analyses were performed using logistic regression, Kaplan-Meier methods, and multivariable Cox proportional hazard models.\n\n\nRESULTS\nOne hundred and eighty-four patients were included in the analysis. The average age was 73years with American Society of Anesthesiology Physical Status Class 2 or 3. Approximately 78% underwent primary debulking surgery (PDS). OS for the entire cohort was 3.3years. One hundred and fifty-seven patients received adjuvant chemotherapy, of which 70% received initial platinum-based doublet therapy; 67.5% of patients were able to complete the intended six cycles of chemotherapy; of these, 34% experienced a dose reduction and 45% experienced one or more dose delays. Any dose delay was associated with a decrease in overall survival (p=0.02) and remained significant even after controlling for age, stage, and residual disease and number of chemotherapy cycles received (p=0.029).\n\n\nCONCLUSIONS\nElderly EOC patients frequently required chemotherapy dose reductions and delays in chemotherapy administration. Multivariate analysis confirmed that dose delays are an independent factor associated with decreased OS.", "affiliations": "Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].", "authors": "Joseph\|Naima\|N\|;Clark\|Rachel M\|RM\|;Dizon\|Don S\|DS\|;Lee\|Malinda S\|MS\|;Goodman\|Annekathryn\|A\|;Boruta\|David\|D\|;Schorge\|John O\|JO\|;Del Carmen\|Marcela G\|MG\|;Growdon\|Whitfield B\|WB\|", "chemical_list": "D009944:Organoplatinum Compounds", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0090-8258", "issue": "137(3)", "journal": "Gynecologic oncology", "keywords": "Chemotherapy; Dose delay; Elderly; Ovarian cancer", "medline_ta": "Gynecol Oncol", "mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial; D009503:Neutropenia; D009944:Organoplatinum Compounds; D010051:Ovarian Neoplasms; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D061665:Time-to-Treatment", "nlm_unique_id": "0365304", "other_id": null, "pages": "401-5", "pmc": null, "pmid": "25839911", "pubdate": "2015-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer.", "title_normalized": "delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer" }	[ { "companynumb": "US-ROCHE-1775520", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN EPITHELIAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN EPITHELIAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN EPITHELIAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal obstruction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure congestive", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Influenza", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device related infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diverticulitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Clostridium difficile infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Embolism venous", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOSEPH J, CLARK R, DIZON D, LEE M, GOODMAN A, BORUTA D, SCHORGE J AND DEL CARMEN M AND GROWDON W. DELAY IN CHEMOTHERAPY ADMINISTRATION IMPACTS SURVIVAL IN ELDERLY PATIENTS WITH EPITHELIAL OVARIAN CANCER.. GYNECOLOGIC ONCOLOGY 2015;137(3):401-405.", "literaturereference_normalized": "delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160615", "receivedate": "20160615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12470016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "Congenital sideroblastic anemia (CSA) is a rare hereditary disease causing disorders of hemoglobin synthesis. Severe, progressive congenital sideroblastic anemia becomes transfusion dependent and results in iron overload. In such cases, patients must undergo stem cell transplantation (SCT) before critical organ dysfunction occurs. However, there has been no consensus on the criteria for SCT for congenital sideroblastic anemia. A 17-year-old Japanese boy was newly diagnosed with congenital sideroblastic anemia manifesting dyspnea on effort. His gene analysis revealed ALAS2 R170L. He gradually become dependent on RBC transfusion. Vitamin B6 (pyridoxal, 30 mg/day) therapy and high-dose alpha-linoleic acid supplementation (150 mg/day) had not been effective. We treated the patient with reduced-intensity SCT from a human leukocyte antigen (HLA) alle 8/8-identical unrelated female donor. The preparation regimen applied consisted of cyclophosphamide, fludarabine, total body irradiation (2 Gy), and anti-thymocyte globulin. We experienced secondary graft failure, nevertheless we used enough immunosuppression. Here we discuss the optimal transplantation regimen for an adult-onset congenital sideroblastic anemia patient with transfusion dependency and mild hemosiderosis. We consider a positive indication for SCT in younger (< 20-year-old) patients with congenital sideroblastic anemia with transfusion dependency. Each case should be individually considered for their suitability for SCT depending on the feasibility and the clinical condition of the patient.", "affiliations": "a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.;a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.;a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.;a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.", "authors": "Imataki\|Osamu\|O\|;Uchida\|Shumpei\|S\|;Uemura\|Makiko\|M\|;Kadowaki\|Norimitsu\|N\|", "chemical_list": "D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human", "country": "England", "delete": false, "doi": "10.1080/08880018.2019.1578844", "fulltext": null, "fulltext_license": null, "issn_linking": "0888-0018", "issue": "36(1)", "journal": "Pediatric hematology and oncology", "keywords": null, "medline_ta": "Pediatr Hematol Oncol", "mesh_terms": "D000624:5-Aminolevulinate Synthetase; D000293:Adolescent; D064591:Allografts; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic; D006084:Graft Rejection; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D033581:Stem Cell Transplantation", "nlm_unique_id": "8700164", "other_id": null, "pages": "46-51", "pmc": null, "pmid": "30912988", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Graft failure after reduced-intensity stem cell transplantation for congenital sideroblastic anemia.", "title_normalized": "graft failure after reduced intensity stem cell transplantation for congenital sideroblastic anemia" }	[ { "companynumb": "JP-MYLANLABS-2019M1049010", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MILLIGRAM/SQ. 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GRAFT FAILURE AFTER REDUCED-INTENSITY STEM CELL TRANSPLANTATION FOR CONGENITAL SIDEROBLASTIC ANEMIA. 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GRAFT FAILURE AFTER REDUCED-INTENSITY STEM CELL TRANSPLANTATION FOR CONGENITAL SIDEROBLASTIC ANEMIA. PEDIATR HEMATOL ONCOL. 2019?23-JAN? 36(1):46-51", "literaturereference_normalized": "graft failure after reduced intensity stem cell transplantation for congenital sideroblastic anemia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190606", "receivedate": "20190606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16396982, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]
{ "abstract": "We report a case of junctional rhythm that occurred both preoperatively and later during a portion of general anesthesia. A 19-year-old woman was scheduled to undergo bilateral sagittal split ramus osteotomy after being diagnosed with a jaw deformity. Preoperative electrocardiography (ECG) revealed a junctional rhythm with a slow heart rate (HR). At 90 minutes after anesthesia induction, local anesthesia with 10 mL of 1% lidocaine and 1:100,000 adrenaline was administered. A junctional rhythm appeared 15 minutes after the local anesthesia. We believe that the atrioventricular nodal pacemaker cells accelerated because of the increased sympathetic activity due to the adrenaline. On the preoperative ECG, the junctional rhythm with slow HR appeared as an escaped beat caused by slowing of the primary pacemaker. Therefore, we think that the preoperative junctional rhythm and the junctional rhythm that appeared during general anesthesia were due to different causes. Understanding the cause of a junctional rhythm could lead to more appropriate treatment. We therefore believe that identifying the cause of the junctional rhythm is important in anesthetic management.", "affiliations": "Department of Anesthesiology, Osaka Dental University, Osaka, Japan.;Department of Anesthesiology, Osaka Dental University, Osaka, Japan.;Department of Anesthesiology, Osaka Dental University, Osaka, Japan.", "authors": "Kishimoto\|Naotaka\|N\|;Kinoshita\|Ikue\|I\|;Momota\|Yoshihiro\|Y\|", "chemical_list": "D008012:Lidocaine; D004837:Epinephrine", "country": "United States", "delete": false, "doi": "10.2344/anpr-64-03-08", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-3006", "issue": "64(3)", "journal": "Anesthesia progress", "keywords": "Adrenaline; Arrhythmia; Atrioventricular node; General anesthesia; Junctional rhythm", "medline_ta": "Anesth Prog", "mesh_terms": "D000768:Anesthesia, General; D001145:Arrhythmias, Cardiac; D001919:Bradycardia; D004562:Electrocardiography; D004837:Epinephrine; D005260:Female; D006801:Humans; D008012:Lidocaine; D019647:Oral Surgical Procedures; D057234:Preoperative Period; D055815:Young Adult", "nlm_unique_id": "0043533", "other_id": null, "pages": "165-167", "pmc": null, "pmid": "28858547", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "5044017;15242446;17180134;6336804;16548866;19243330;3970369", "title": "Junctional Rhythm Preoperatively and During General Anesthesia for Oral and Maxillofacial Surgery.", "title_normalized": "junctional rhythm preoperatively and during general anesthesia for oral and maxillofacial surgery" }	[ { "companynumb": "JP-MYLANLABS-2018M1048745", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019430", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1:100000 ; 12ML (LIDOCAINE ALONG WITH EPINEPHRINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 ML (LIDOCAINE ALONG WITH EPINEPHRINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AND 10 ML (LIDOCAINE ALONG WITH EPINEPHRINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "REMIFENTANIL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.1?0.15 MICROG/KG/MIN ; INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMIFENTANIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019430", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1:100000 ; 10 ML (LIDOCAINE ALONG WITH EPINEPHRINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ROCURONIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROCURONIUM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4.5?5.0 MICROG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MICROG", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MICROG/ML ; PROPOFOL INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "REMIFENTANIL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MICROG/KG/MIN; INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMIFENTANIL" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "50", "reaction": [ { "reactionmeddrapt": "Nodal rhythm", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KISHIMOTO N, KINOSHITA I, MOMOTA Y. JUNCTIONAL RHYTHM PREOPERATIVELY AND DURING GENERAL ANESTHESIA FOR ORAL AND MAXILLOFACIAL SURGERY. ANESTH?PROG 2017?64(3):165?167.", "literaturereference_normalized": "junctional rhythm preoperatively and during general anesthesia for oral and maxillofacial surgery", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180706", "receivedate": "20180706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15117410, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "This study evaluates the frequency and causes of dolutegravir (DTG) discontinuation along 5 years of follow-up, in both antiretroviral treatment (ART)-naive and experienced people living with HIV (PLWH). This is a prospective multi-center cohort study enrolling PLWH on DTG from July 2014 until November 2020. DTG-durability was investigated using the Kaplan-Meier survival curve. The Cox proportional-hazards model was used for estimating the hazard ratio (HR) of DTG discontinuation for any cause, and for adverse events (AEs). Nine hundred sixty-three PLWH were included, 25.3% were women and 28.0% were ART-naive. Discontinuations for any causes were 10.1 [95% confidence interval (95% CI) 8.9-11.5] per 100 person-years, similar in most regimens, with the apparent exception of tenofovir alafenamide/emtricitabine+DTG (p < 0.0001). In the multivariable Cox regression model, non-Caucasian ethnicity, age ≥50 years, and lower estimated glomerular filtration rate (eGFR) were associated with a higher probability of DTG interruption. The incidence rate of virological failure was 0.4 (95% CI 0.2-0.7) per 100 person-years, while the estimated discontinuation rate for AEs was 4.0 (3.2-4.9) per 100 person-years. Thirty-four DTG interruptions were due to grade ≥3 events (10 central nervous system, 6 hypersensitivity, 3 renal, 3 myalgia/asthenia, 3 abdominal pain, 2 gastrointestinal, and 7 other events). People with lower body mass index, age ≥50 years, and lower eGFR were at higher risk of AEs, while dual combinations were protective (HR 0.41 compared with abacavir/lamivudine/DTG, 95% CI 0.22-0.77). In this prospective observational study, we found high DTG durability and a low rate of virological failures. Dual therapies seemed protective toward AEs and might be considered, when feasible, a suitable option to minimize drug interactions and improve tolerability.", "affiliations": "Infectious Disease Clinic, IRCCS Policlinico San Martino Hospital, Genoa, Italy.;Unit of Infectious and Tropical Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.;Fondazione ASIA Onlus, Buccinasco, Italy.;Unit of Infectious Diseases, \"Divisione A\", Amedeo di Savoia Hospital, Torino, Italy.;Infectious Diseases Clinic, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.;Unit of Infectious Diseases, ASST della Valle Olona, Busto Arsizio Hospital, Busto Arsizio, Italy.;Infectious Disease Unit, Ospedale A. Manzoni, Lecco, Italy.;Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.;Clinic of Infectious Diseases, Department of Medicine 2, Azienda Ospedaliera di Perugia, Santa Maria Hospital, Perugia, Italy.;Unit of Infectious Diseases, Department of Human Pathology of the Adult and the Developmental Age 'G. Barresi', University of Messina, Messina, Italy.;Infectious Diseases Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.;Unit of Infectious Diseases, University of Catania, ARNAS Garibaldi, Catania, Italy.;Department of Medical and Surgical Sciences, Clinics of Infectious Diseases, S. Orsola-Malpighi Hospital, \"Alma Mater Studiorum\" University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Biomedical and Clinical Sciences 'Luigi Sacco', Università degli Studi di Milano, Milan, Italy.;Infectious Disease Unit (I Divisione), ASST Fatebenefratelli Sacco, Milan, Italy.;SOD Malattie Infettive e Tropicali AOU Careggi, Florence, Italy.;Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.;Department of Infectious Disease, University of Campania Luigi Vanvitelli, Naples, Italy.;Infectious Diseases Department, SOC 1, USLCENTROFIRENZE, Santa Maria Annunziata Hospital, Florence, Italy.;Infectious Diseases Unit, SS Trinità Hospital, Cagliari, Italy.;Department of Infectious and Tropical Diseases, St. Annunziata Hospital, Cosenza, Italy.;Infectious Diseases Department, Sanremo Hospital, Sanremo, Italy.;Infectious Disease Clinic, IRCCS Policlinico San Martino Hospital, Genoa, Italy.;Infectious Disease Unit, Department of Internal Medicine, Fondazione IRCCS Ca' Granda, University of Milan, Ospedale Maggiore Policlinico, Milan, Italy.;Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy.;Infectious Diseases Clinic, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.;Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, San Martino Hospital-IRCCS, Genoa, Italy.;Unit of Infectious and Tropical Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.", "authors": "Taramasso\|Lucia\|L\|0000-0002-6622-6358;De Vito\|Andrea\|A\|;Ricci\|Elena Delfina\|ED\|;Orofino\|Giancarlo\|G\|;Squillace\|Nicola\|N\|;Menzaghi\|Barbara\|B\|;Molteni\|Chiara\|C\|;Gulminetti\|Roberto\|R\|;De Socio\|Giuseppe Vittorio\|GV\|;Pellicanò\|Giovanni Francesco\|GF\|;Sarchi\|Eleonora\|E\|;Celesia\|Benedetto Maurizio\|BM\|;Calza\|Leonardo\|L\|;Rusconi\|Stefano\|S\|;Valsecchi\|Laura\|L\|;Martinelli\|Canio Vito\|CV\|;Cascio\|Antonio\|A\|;Maggi\|Paolo\|P\|;Vichi\|Francesca\|F\|;Angioni\|Goffredo\|G\|;Guadagnino\|Giuliana\|G\|;Cenderello\|Giovanni\|G\|;Dentone\|Chiara\|C\|;Bandera\|Alessandra\|A\|;Falasca\|Katia\|K\|;Bonfanti\|Paolo\|P\|;Di Biagio\|Antonio\|A\|;Madeddu\|Giordano\|G\|;\|\|\|", "chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir", "country": "United States", "delete": false, "doi": "10.1089/apc.2021.0089", "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2914", "issue": "35(9)", "journal": "AIDS patient care and STDs", "keywords": "HIV; adverse events; dolutegravir; durability; safety; toxicity; virolgical failure", "medline_ta": "AIDS Patient Care STDS", "mesh_terms": "D019380:Anti-HIV Agents; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011446:Prospective Studies; D011728:Pyridones", "nlm_unique_id": "9607225", "other_id": null, "pages": "342-353", "pmc": null, "pmid": "34524918", "pubdate": "2021-09", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Durability of Dolutegravir-Based Regimens: A 5-Year Prospective Observational Study.", "title_normalized": "durability of dolutegravir based regimens a 5 year prospective observational study" }	[ { "companynumb": "IT-VIIV HEALTHCARE LIMITED-IT2021GSK198805", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ABACAVIR SULFATE\\DOLUTEGRAVIR SODIUM\\LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "205551", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABACAVIRSULPHATE+DOLUTEGRAVIR+LAMIVUDINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Electrocardiogram QT prolonged", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TARAMASSO L, DE VITO A, RICCI ED, OROFINO G, SQUILLACE N, MENZAGHI B ET AL.. DURABILITY OF DOLUTEGRAVIR?BASED REGIMENS: A 5?YEAR PROSPECTIVE OBSERVATIONAL STUDY. AIDS PATIENT CARE AND STDS. 2021?35 (9):342?353", "literaturereference_normalized": "durability of dolutegravir based regimens a 5 year prospective observational study", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210930", "receivedate": "20210930", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19906117, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Current lymphogranuloma venereum (LGV) guidelines mainly focus on anorectal infections. Inguinal LGV infections have been rare in the current epidemic among men who have sex with men (MSM), but might require a different approach not yet recommended in current guidelines for the treatment and diagnosis of LGV. We describe 4 inguinal LGV cases. Three MSM developed inguinal LGV infection several weeks after a previous consultation, of which two had received azithromycin after being notified for LGV. Three failed the recommended 21 days doxycycline treatment. These inguinal LGV cases highlight 3 pitfalls in the current standard management of LGV: (1) Urethral chlamydia infections in MSM can be caused by LGV biovars that in contrast to non-LGV biovars require prolonged antibiotic therapy. (2) The recommended one gram azithromycin contact treatment seems insufficient to prevent established infections. (3) Inguinal LGV may require prolonged courses of doxycycline, exceeding the currently advised 21 days regimen.", "affiliations": "Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands.;General Practitioners Office Heijnen & de Meij, Amsterdam, The Netherlands.;Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands The Netherlands STI Outpatient Clinic, Public Health Service Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.", "authors": "Oud\|Emerentiana Veronica\|EV\|;de Vrieze\|Nynke Hesselina Neeltje\|NH\|;de Meij\|Arjan\|A\|;de Vries\|Henry John C\|HJ\|", "chemical_list": "D000900:Anti-Bacterial Agents; D017963:Azithromycin; D004318:Doxycycline", "country": "England", "delete": false, "doi": "10.1136/sextrans-2013-051427", "fulltext": null, "fulltext_license": null, "issn_linking": "1368-4973", "issue": "90(4)", "journal": "Sexually transmitted infections", "keywords": "Human immunodeficiency virus; Lymphogranuloma venereum; Men who have sex with men; Sexually transmitted infection", "medline_ta": "Sex Transm Infect", "mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002690:Chlamydia Infections; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline; D015658:HIV Infections; D006526:Hepatitis C; D018451:Homosexuality, Male; D006801:Humans; D007264:Inguinal Canal; D008219:Lymphogranuloma Venereum; D008297:Male; D008875:Middle Aged; D017211:Treatment Failure; D014522:Urethral Diseases", "nlm_unique_id": "9805554", "other_id": null, "pages": "279-82", "pmc": null, "pmid": "24787368", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum: important lessons from a case series.", "title_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series" }	[ { "companynumb": "NL-ACTAVIS-2014-16198", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "1000 MG TWICE", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENITOURINARY CHLAMYDIA INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065041", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LYMPHOGRANULOMA VENEREUM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE MONOHYDRATE (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LYMPHOGRANULOMA VENEREUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug effect delayed", "reactionmeddraversionpt": "17.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "17.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "OUD EV, DE VRIEZE NH, DE MEIJ A, DE VRIES HJ. PITFALLS IN THE DIAGNOSIS AND MANAGEMENT OF INGUINAL LYMPHOGRANULOMA VENEREUM: IMPORTANT LESSONS FROM A CASE SERIES. SEX TRANSM INFECT. 2014;90(4):279-82", "literaturereference_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20140729", "receivedate": "20140729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10348057, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "NL-ACTAVIS-2014-16209", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065041", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LYMPHOGRANULOMA VENEREUM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE MONOHYDRATE (UNKNOWN)" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "065041", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE MONOHYDRATE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug effect delayed", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OUD EV, DE VRIEZE NH, DE MEIJ A, DE VRIES HJ. PITFALLS IN THE DIAGNOSIS AND MANAGEMENT OF INGUINAL LYMPHOGRANULOMA VENEREUM: IMPORTANT LESSONS FROM A CASE SERIES. SEX TRANSM INFECT. 2014;90(4):279-82", "literaturereference_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20140729", "receivedate": "20140729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10348050, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "NL-ACTAVIS-2014-16208", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065041", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LYMPHOGRANULOMA VENEREUM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE MONOHYDRATE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug effect delayed", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OUD EV, DE VRIEZE NH, DE MEIJ A, DE VRIES HJ. PITFALLS IN THE DIAGNOSIS AND MANAGEMENT OF INGUINAL LYMPHOGRANULOMA VENEREUM: IMPORTANT LESSONS FROM A CASE SERIES. SEX TRANSM INFECT. 2014;90(4):279-82", "literaturereference_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20140729", "receivedate": "20140729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10348053, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]
{ "abstract": "Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib.\n\n\n\nThis phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib.\n\n\n\nWhen a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed.\n\n\n\nThe addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers.\n\n\n\nClinicalTrials.gov identifier, NCT02804399.", "affiliations": "Global Product Development, Pfizer Oncology, New York, NY, USA. [email protected].;Global Product Development, Clinical Pharmacology, Pfizer Oncology, La Jolla, CA, USA.;Global Product Development, Pfizer Inc., New Haven, CT, USA.;Global Product Development, Pfizer Oncology, New York, NY, USA.;Safety Surveillance and Risk Management, Pfizer Oncology, Groton, CT, USA.;Global Product Development, Pfizer Inc., Groton, CT, USA.;Global Product Development, Pfizer Inc., South Lyon, MI, USA.;Global Product Development, Pfizer Inc., Groton, CT, USA.;Global Product Development, Clinical Pharmacology, Pfizer Oncology, La Jolla, CA, USA.", "authors": "Chen\|Joseph\|J\|http://orcid.org/0000-0002-5998-7765;Xu\|Huiping\|H\|;Pawlak\|Sylvester\|S\|;James\|Leonard P\|LP\|;Peltz\|Gerson\|G\|;Lee\|Kimberly\|K\|;Ginman\|Katherine\|K\|;Bergeron\|Michelle\|M\|;Pithavala\|Yazdi K\|YK\|", "chemical_list": "D000631:Aminopyridines; D000970:Antineoplastic Agents; D007769:Lactams; D047029:Lactams, Macrocyclic; D011720:Pyrazoles; C000590786:lorlatinib; D012293:Rifampin", "country": "United States", "delete": false, "doi": "10.1007/s12325-019-01198-9", "fulltext": null, "fulltext_license": null, "issn_linking": "0741-238X", "issue": "37(2)", "journal": "Advances in therapy", "keywords": "Drug–drug interaction; Healthy participants; Lorlatinib; Pharmacokinetics; Rifampin; Safety", "medline_ta": "Adv Ther", "mesh_terms": "D000328:Adult; D000631:Aminopyridines; D000970:Antineoplastic Agents; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D012293:Rifampin; D055815:Young Adult", "nlm_unique_id": "8611864", "other_id": null, "pages": "745-758", "pmc": null, "pmid": "31863284", "pubdate": "2020-02", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.", "title_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants" }	[ { "companynumb": "US-MYLANLABS-2020M1036999", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665174, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037008", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "600 MILLIGRAM(2 CAPSULES OF 300MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665187, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037010", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE WITH APPROXIMATELY 240ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665267, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037006", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED ...", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665176, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037012", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100MG (ADMINISTERED..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037005", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE...", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665186, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037014", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE WITH..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17669606, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037283", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665262, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037000", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE WITH APPROXIMATELY 240ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665172, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037203", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17666160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037004", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17669605, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037002", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665175, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]
{ "abstract": "A 6 month-old-female infant from Bahrain visiting Germany with her family for a holiday was seen by us for extensive dermatophytosis of the back, buttocks, chest and groins. Topical treatment by terbinafine for over 2 months was not successful. Other family members including adults and children were treated in Bahrain with topical antifungals and oral voriconazole which was not helpful. Mycological examination performed in Germany revealed the detection of the zoophilic dermatophyte Trichophyton (T.) mentagrophytes. The newly described genotype VIII within the species T. mentagrophytes was identified by sequencing of the \"internal transcribed spacer\" (ITS) region of the fungal rDNA. This genotype of T. mentagrophytes is the main causative agent of the current epidemic of chronic recalcitrant dermatophytoses in India. Transmission of this Indian genotype of T. mentagrophytes to other countries due to globalization is a serious issue to be considered. Moreover, a significant percentage of these Indian T. mentagrophytes strains are resistant to terbinafine both in vitro and by the way of genetic point mutations in the squalene epoxidase (SQLE) gene. Some are also found to be partially resistant against itraconazole and voriconazole. The point mutation TTC/TTA was found by SQLE mutation analysis in this particular T. mentagrophyte isolate from Bahrain. This point mutation is closely associated with F397L amino acid substitution of the enzyme indicative of in vitro resistance of the dermatophyte against terbinafine. The girl was successfully treated by topical miconazole and later by ciclopirox olamine. This is the first report on an infection due to a terbinafine-resistant T. mentagrophytes strain of the ITS genotype VIII from India in Germany.", "affiliations": "Hautärztin, Gemeinschaftspraxis Allgemeinmedizin und Dermatologie, Kurfürstenstr. 23a, 54616, Wittlich, Deutschland.;Labor für Medizinische Mikrobiologie, Mölbiser Hauptstr. 8, 04571, Rötha OT Mölbis, Deutschland.;Allgemeinmedizinische Praxis Dr. med. Alfons Ludes und Thorsten Koech, Poststr, 5, 54340, Leiwen, Deutschland.;\"Nirvan\" and \"In Skin\" Clinics, Vadodara, Gujarat, Indien.;Dermatology Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Schweiz.;Labor für Medizinische Mikrobiologie, Mölbiser Hauptstr. 8, 04571, Rötha OT Mölbis, Deutschland.;Labor für Medizinische Mikrobiologie, Mölbiser Hauptstr. 8, 04571, Rötha OT Mölbis, Deutschland. [email protected].", "authors": "Süß\|Anke\|A\|;Uhrlaß\|Silke\|S\|;Ludes\|Alfons\|A\|;Verma\|Shyam B\|SB\|;Monod\|Michel\|M\|;Krüger\|Constanze\|C\|;Nenoff\|Pietro\|P\|", "chemical_list": "D000935:Antifungal Agents; D012331:RNA, Fungal; D000077768:Ciclopirox; D008825:Miconazole; D000077291:Terbinafine", "country": "Germany", "delete": false, "doi": "10.1007/s00105-019-4431-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0017-8470", "issue": "70(11)", "journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete", "keywords": "Ciclopirox olamine; Dermatomycoses; Miconazole; Mutation analysis; Point mutation", "medline_ta": "Hautarzt", "mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001445:Bahrain; D000077768:Ciclopirox; D005260:Female; D005838:Genotype; D005858:Germany; D006801:Humans; D007223:Infant; D008825:Miconazole; D012331:RNA, Fungal; D017423:Sequence Analysis, RNA; D000077291:Terbinafine; D014005:Tinea; D014006:Tinea Capitis; D014249:Trichophyton", "nlm_unique_id": "0372755", "other_id": null, "pages": "888-896", "pmc": null, "pmid": "31098692", "pubdate": "2019-11", "publication_types": "D016428:Journal Article", "references": "30284315;27783317;29722887;30187579;29577447;30507401;30275090;28416557;27071492;29512606;29893296;29485088;30561859;26886443;28584364;29706004;22587730;29976522;23532505", "title": "Extensive tinea corporis due to a terbinafine-resistant Trichophyton mentagrophytes isolate of the Indian genotype in a young infant from Bahrain in Germany.", "title_normalized": "extensive tinea corporis due to a terbinafine resistant trichophyton mentagrophytes isolate of the indian genotype in a young infant from bahrain in germany" }	[ { "companynumb": "DE-GLAXOSMITHKLINE-DE2020GSK211646", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERBINAFINE" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": "020749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRICHOPHYTOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERBINAFINE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pathogen resistance", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SUB A, UHRLAB S, LUDES A, VERMA SB, MONOD M, KRUGER C ET AL.. EXTENSIVE TINEA CORPORIS DUE TO A TERBINAFINE-RESISTANT TRICHOPHYTON MENTAGROPHYTES ISOLATE OF THE INDIAN GENOTYPE IN A YOUNG INFANT FROM BAHRAIN IN GERMANY. DER HAUTARZT? ZEITSCHRIFT FUR DERMATOLOGIE, VENEROLOGIE, UND VERWANDTE GEBIETE. 2019?70 (11):888-896", "literaturereference_normalized": "extensive tinea corporis due to a terbinafine resistant trichophyton mentagrophytes isolate of the indian genotype in a young infant from bahrain in germany", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201104", "receivedate": "20201104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18462884, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]
{ "abstract": "Human T-lymphotropic virus type I (HTLV-I) is a retrovirus associated with adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to HAM/TSP and ATL, HTLV-I-associated encephalopathy and cerebellar involvement have been reported. We report a case of an 87-year-old Japanese woman presenting with progressive dysarthria and gait disturbance. Neurological examination showed word-finding difficulty, scanning speech, saccadic eye movements, ocular dysmetria, gaze-evoked nystagmus and bilateral dysmetria. There was no motor weakness or spasticity. HTLV-I antibody was detected in both her serum and cerebrospinal fluid. Cerebrospinal fluid neopterin (57 pg/mL) and IgG index (3.27) were significantly elevated. MRI showed cerebellar swelling. She was finally diagnosed with HTLV-I associated cerebellitis. Two courses of high-dose intravenous methylpredonine therapy attenuated cerebellar ataxia and cerebellar swelling. It suggests that cerebellitis can result from HTLV-I infection, regardless of the existence of ATL or HAM/TSP.", "affiliations": "Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan [email protected].;Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.;Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.;Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.", "authors": "Mizuma\|Atsushi\|A\|;Enokida\|Kumiko\|K\|;Nagata\|Eiichiro\|E\|;Takizawa\|Shunya\|S\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2020-241366", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(6)", "journal": "BMJ case reports", "keywords": "brain stem / cerebellum; infection (neurology)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D002524:Cerebellar Ataxia; D005260:Female; D015490:HTLV-I Infections; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D009759:Nystagmus, Pathologic; D015493:Paraparesis, Tropical Spastic", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "34099448", "pubdate": "2021-06-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cerebellitis in a human T-lymphotropic virus type 1 carrier: a case report.", "title_normalized": "cerebellitis in a human t lymphotropic virus type 1 carrier a case report" }	[ { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2021SP026223", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "210785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": 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CEREBELLITIS IN A HUMAN T?LYMPHOTROPIC VIRUS TYPE 1 CARRIER: A CASE REPORT. 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CEREBELLITIS IN A HUMAN T?LYMPHOTROPIC VIRUS TYPE 1 CARRIER: A CASE REPORT. BMJ?CASE?REP 2021?14(6):E241366.", "literaturereference_normalized": "cerebellitis in a human t lymphotropic virus type 1 carrier a case report", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210825", "receivedate": "20210825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19742125, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-MYLANLABS-2021M1050523", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH?DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENCEPHALITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENCEPHALITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Interleukin-2 receptor increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adult T-cell lymphoma/leukaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIZUMA A, ENOKIDA K, NAGATA E, TAKIZAWA S. CEREBELLITIS IN A HUMAN T?LYMPHOTROPIC VIRUS TYPE 1 CARRIER: A CASE REPORT. BMJ?CASE?REP 2021?14(6):E241366.. 2021?14(6):E241366", "literaturereference_normalized": "cerebellitis in a human t lymphotropic virus type 1 carrier a case report", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210914", "receivedate": "20210813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19700523, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]
{ "abstract": "Non-vitamin K oral anticoagulants (NOACs) are being increasingly prescribed. These drugs act rapidly, have predictable dose-related anticoagulation effect and require no routine laboratory monitoring, making them attractive for both patients and healthcare providers. All NOACs are at least partially excreted thought the kidneys. Renal injury related to NOAC use is being increasingly reported. NOAC-related acute interstitial nephritis (AIN) has only been reported once and that was in context of dabigatran use. We describe the first case of apixaban-related AIN. This case adds an important differential diagnoses that should be considered for any patient presenting with renal injury while being treated with NOACs.", "affiliations": "Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.", "authors": "Abdulhadi\|Basma\|B\|http://orcid.org/0000-0003-2359-6612;Mulki\|Ramzi\|R\|;Goyal\|Abhinav\|A\|;Rangaswami\|Janani\|J\|", "chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-221641", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "acute renal failure; drugs and medicines; renal system", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D003937:Diagnosis, Differential; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D009395:Nephritis, Interstitial; D011720:Pyrazoles; D011728:Pyridones", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28847995", "pubdate": "2017-08-28", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12825841;18832478;24859719;26144101;26347498;26670286;26698882;26885473;4176988", "title": "Novel oral anticoagulant and kidney injury: apixaban-related acute interstitial nephritis.", "title_normalized": "novel oral anticoagulant and kidney injury apixaban related acute interstitial nephritis" }	[ { "companynumb": "US-PFIZER INC-2017411494", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "APIXABAN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APIXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL TARTRATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "074133", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL TARTRATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIFEDIPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018482", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIFEDIPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018972", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDRALAZINE APS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GLIPIZIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIPIZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020702", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN CALCIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SILDENAFIL CITRATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021845", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILDENAFIL CITRATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ABDULHADI, B.. NOVEL ORAL ANTICOAGULANT AND KIDNEY INJURY: APIXABAN-RELATED ACUTE INTERSTITIAL NEPHRITIS.. BMJ CASE REPORTS. 2017?10.1136/BCR-2017-221641", "literaturereference_normalized": "novel oral anticoagulant and kidney injury apixaban related acute interstitial nephritis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180529", "receivedate": "20171004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14038991, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "This is a report on two cases of refractory schizophrenia and two cases of clozapine-resistant schizophrenia successful treated with paliperidone palmitate. To the authors' knowledge, this is the first report of the successful use of paliperidone palmitate in such patients.", "affiliations": "From the Hospital das Clínicas, Monte Alegre, Ribeirão Preto, São Paulo, Brazil; the University of São Paulo; the Dept. of Psychiatry, Federal University of São Paulo; and the Dept. of Neuroscience and Behavior, School of Medicine of Ribeirão Preto, São Paulo, Brazil.", "authors": "Maia-de-Oliveira\|João Paulo\|JP\|;Nunes\|Emerson Arcoverde\|EA\|;Ushirohira\|Juliana Mayumi\|JM\|;Machado-de-Sousa\|João Paulo\|JP\|;Bressan\|Rodrigo Affosenca\|RA\|;Hallak\|Jaime Eduardo Cecílio\|JE\|", "chemical_list": "D014150:Antipsychotic Agents; D007555:Isoxazoles; D010168:Palmitates; D003024:Clozapine; D000068882:Paliperidone Palmitate", "country": "United States", "delete": false, "doi": "10.1176/appi.neuropsych.13120374", "fulltext": null, "fulltext_license": null, "issn_linking": "0895-0172", "issue": "27(1)", "journal": "The Journal of neuropsychiatry and clinical neurosciences", "keywords": null, "medline_ta": "J Neuropsychiatry Clin Neurosci", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D005260:Female; D006801:Humans; D007555:Isoxazoles; D008297:Male; D000068882:Paliperidone Palmitate; D010168:Palmitates; D012559:Schizophrenia; D055815:Young Adult", "nlm_unique_id": "8911344", "other_id": null, "pages": "e14-6", "pmc": null, "pmid": "25716490", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Paliperidone palmitate for refractory and clozapine-resistant schizophrenia.", "title_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia" }	[ { "companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-106734", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071156", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT APPROPRIATE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT APPROPRIATE DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MAIA-DE-OLIVEIRA JP, NUNES EA, USHIROHIRA JM, MACHADO-DE-SOUSA JP, BRESSAN RA, HALLAK JEC. PALIPERIDONE PALMITATE FOR REFRACTORY AND CLOZAPINE-RESISTANT SCHIZOPHRENIA. J-NEUROPSYCHIATRY-CLIN-NEUROSCI. 2015?27(1):E14-E16", "literaturereference_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20151203", "receivedate": "20151203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11796487, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "PHHY2015BR141781", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORPROMAZINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "80439", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORPROMAZINE." } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAIA-DE-OLIVEIRA JP, NUNES EA, USHIROHIRA JM, MACHADO-DE-SOUSA JP, BRESSAN RA, HALLAK JEC.. PALIPERIDONE PALMITATE FOR REFRACTORY AND CLOZAPINE-RESISTANT SCHIZOPHRENIA.. J-NEUROPSYCHIATRY-CLIN-NEUROSCI.. 2015?27(1):E14-16", "literaturereference_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20151103", "receivedate": "20151103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11694089, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-106739", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071156", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dystonia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Parkinsonism", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAIA-DE-OLIVEIRA JP, NUNES EA, USHIROHIRA JM, MACHADO-DE-SOUSA JP, BRESSAN RA, HALLAK JEC. PALIPERIDONE PALMITATE FOR REFRACTORY AND CLOZAPINE-RESISTANT SCHIZOPHRENIA. J-NEUROPSYCHIATRY-CLIN-NEUROSCI. 2015?27(1):E14-E16", "literaturereference_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20151203", "receivedate": "20151203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11796482, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-106740", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperprolactinaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAIA-DE-OLIVEIRA JP, NUNES EA, USHIROHIRA JM, MACHADO-DE-SOUSA JP, BRESSAN RA, HALLAK JEC. PALIPERIDONE PALMITATE FOR REFRACTORY AND CLOZAPINE-RESISTANT SCHIZOPHRENIA. J-NEUROPSYCHIATRY-CLIN-NEUROSCI. 2015?27(1):E14-E16", "literaturereference_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20151203", "receivedate": "20151203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11796481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-106738", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071156", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy cessation", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": null }, { "reactionmeddrapt": "Schizophrenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAIA-DE-OLIVEIRA JP, NUNES EA, USHIROHIRA JM, MACHADO-DE-SOUSA JP, BRESSAN RA, HALLAK JEC. PALIPERIDONE PALMITATE FOR REFRACTORY AND CLOZAPINE-RESISTANT SCHIZOPHRENIA. J-NEUROPSYCHIATRY-CLIN-NEUROSCI. 2015?27(1):E14-E16", "literaturereference_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20151203", "receivedate": "20151203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11796483, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]
{ "abstract": "BACKGROUND\nAssociation of leukoencephalopathy and atypical mycobacteriosis has been rarely reported. We present a case that is relevant for its unusual presentation and because it may shed further light on the pathogenic mechanisms underlying reversible encephalopathies.\n\n\nMETHODS\nWe report the case of a Hispanic 64-year-old woman with cognitive decline and extensive leukoencephalopathy. Magnetic resonance imaging revealed white-matter lesions with increased water diffusivity, without blood-brain-barrier disruption. Brain biopsy showed tissue rarefaction with vacuolation, mild inflammation, few reactive astrocytes and decreased aquaporin water-channel expression in the lesions. Six months later, she was diagnosed with atypical mycobacterial pulmonary infection. Brain lesions resolved after antimycobacterial treatment.\n\n\nCONCLUSIONS\nWe hypothesize leukoencephalopathic changes and vasogenic edema were associated with decreased aquaporin expression. Further studies should clarify if reversible leukoencephalopathy has a causal relationship with decreased aquaporin expression and atypical mycobacterial infection, and mechanisms underlying leukoencephalopathy resolution after antimycobacterial treatment. This article may contribute to the understanding of pathogenic mechanisms underlying magnetic resonance imaging subcortical lesions and edema, which remain incompletely understood.", "affiliations": "Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Departments of Neurology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Institute of Radiology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Department of Pathology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Multiple Sclerosis Therapeutics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. [email protected].;Multiple Sclerosis Therapeutics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].", "authors": "Oliveira\|Marcos C B\|MC\|;Sato\|Douglas Kazutoshi\|DK\|;Soares-Neto\|Herval R\|HR\|;Lucato\|Leandro T\|LT\|;Callegaro\|Dagoberto\|D\|;Nitrini\|Ricardo\|R\|;Medeiros\|Raphael S S\|RS\|;Misu\|Tatsuro\|T\|;Fujihara\|Kazuo\|K\|;Castro\|Luiz H\|LH\|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "England", "delete": false, "doi": "10.1186/s12883-015-0415-0", "fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 41510.1186/s12883-015-0415-0Case ReportLeukoencephalopathy resolution after atypical mycobacterial treatment: a case report Oliveira Marcos C. B. [email protected] Sato Douglas Kazutoshi [email protected] Soares-Neto Herval R. [email protected] Lucato Leandro T. [email protected] Callegaro Dagoberto [email protected] Nitrini Ricardo [email protected] Medeiros Raphael S. S. [email protected] Misu Tatsuro [email protected] Fujihara Kazuo [email protected] Castro Luiz H. [email protected] Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900 São Paulo, SP Brazil Institute of Radiology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900 São Paulo, SP Brazil Department of Pathology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900 São Paulo, SP Brazil Departments of Neurology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan Multiple Sclerosis Therapeutics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan 2 9 2015 2 9 2015 2015 15 15925 3 2015 25 8 2015 © Oliveira et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAssociation of leukoencephalopathy and atypical mycobacteriosis has been rarely reported. We present a case that is relevant for its unusual presentation and because it may shed further light on the pathogenic mechanisms underlying reversible encephalopathies.\n\nCase report\nWe report the case of a Hispanic 64-year-old woman with cognitive decline and extensive leukoencephalopathy. Magnetic resonance imaging revealed white-matter lesions with increased water diffusivity, without blood–brain-barrier disruption. Brain biopsy showed tissue rarefaction with vacuolation, mild inflammation, few reactive astrocytes and decreased aquaporin water-channel expression in the lesions. Six months later, she was diagnosed with atypical mycobacterial pulmonary infection. Brain lesions resolved after antimycobacterial treatment.\n\nConclusion\nWe hypothesize leukoencephalopathic changes and vasogenic edema were associated with decreased aquaporin expression. Further studies should clarify if reversible leukoencephalopathy has a causal relationship with decreased aquaporin expression and atypical mycobacterial infection, and mechanisms underlying leukoencephalopathy resolution after antimycobacterial treatment. This article may contribute to the understanding of pathogenic mechanisms underlying magnetic resonance imaging subcortical lesions and edema, which remain incompletely understood.\n\nKeywords\nReversible encephalopathy syndromePRESMycobacteriosisLeukoencephalopathyVasogenic edemaAquaporin water-channelissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nReversible leukoencephalopathy is characterized by headaches, seizures, vomiting, and confusion, associated with extensive bilateral white-matter subcortical neuroimaging abnormalities, suggestive of vasogenic edema without infarction [1]. Most cases of reversible encephalopathy are referred to as posterior reversible encephalopathy syndrome (PRES), since white matter changes are more prominent in the posterior cerebral regions. Brainstem, cerebellum and other brain regions may also be affected [2]. PRES has been associated with severe hypertension (including eclampsia), renal dysfunction, infection, autoimune disease, and immunosuppressant drug use [1–7]. The hallmark of PRES is reversible cerebral edema due to blood–brain-barrier dysfunction [8]. Pathogenic mechanisms underlying magnetic resonance imaging (MRI) subcortical lesions and edema remains incompletely understood.\n\nAssociation of brain edema and mycobacteria has previously been reported in the setting of Mycobacterium tuberculosis infection [9–15], and in one patient who presented with acute disseminated encephalomyelitis (ADEM) associated with Mycobacterium intracellulare meningitis, who responded to high dose steroid pulse therapy [16]. In all reported cases of mycobacterial infection associated with edema, underlying mechanisms involved demyelination and inflammation. Association of a non-demyelinating leukoencephalopathy and atypical mycobacteriosis has not, to our knowledge, been previously reported.\n\nWe report neuroimaging and brain histology features of a patient with extensive leukoencephalopathy with brain edema and absence of demyelination, that resolved after atypical mycobacterial pulmonary infection treatment.\n\nCase presentation\nA Hispanic 64-year-old woman was admitted with headaches, vomiting and confusion. A month earlier, the patient presented with subacute new-onset headaches, nausea, vomiting, gait impairment, and anorexia. There was no history of fever, cough, abdominal pain, previous medical disease or immunosuppressant drug use. Blood pressure was normal. Physical examination was unremarkable. Neurologic examination showed an unsteady gait, without motor weakness or ataxia. Cognitive tests showed a Mini-Mental Status Exam (MMSE) score of 18/30, impaired attention, executive functions, verbal fluency and episodic memory (Table 1).Table 1 Cognitive evaluations in a patient with reversible leukoencephalopathy before and after atypical mycobacteria treatment\n\n\tInitial assessment\tFive months after initial assessment (no mycobacterial treatment)\tEighteen months after initial assessment (one year of mycobaterial treatment)\t\nMini Mental State Exam (MMSE)\t18/30\t18/30\t22/30\t\nDigit span (direct/indirect)\t3 / 0\t3 / 0\t4 / 2\t\nShort Memory Test with 10 items (incidental memory / immediate memory / learning)\n\t3 / 7 / 8\t4 / 1 / 1\t5 / 7 / 8\t\nDelayed Memory Test with 10 items (after distraction) without / with hints\n\t6 (1) / 8\t3 / 4 (3)\t8 / 10\t\nVerbal fluency (semantic / phonemic)\t5 (animals) / 1 (letter P)\t6 (animals) / 1 (letter P)\t10 (animals) / 1 (letter P)\t\nClock-drawing test\tDisexecutive: distortion of number placement (4 points)\tDisexecutive: crowding numbers to one side (5 points)\tMore noticeable errors in hand/number placement (8 points)\t\nFunctional Activity Questionnaire (FAQ)\t\t25/30\t10/30\t\nPatient’s education: 4 Years\n\nLegend: Number of intrusions between brackets\n\n\n\nBrain MRI disclosed diffuse and symmetric confluent nonenhancing white matter lesions, that were hyperintense in T2/FLAIR images (Fig. 1a to d). Corresponding apparent diffusion coefficients (ADC) maps suggested vasogenic edema (Fig. 1f). MRI angiography was unremarkable (not shown). Multivoxel spectroscopy, dynamic susceptibility contrast (DSC) perfusion (T2) and dynamic contrast-enhanced (DCE) permeability (T1) did not disclose relevant abnormalities (Fig. 1e, g and h). Cerebrospinal fluid analysis showed a normal cell count (4 cells/mm3), protein (32 mg/dL) and glucose (80 mg/dL) levels, normal protein electrophoresis values, negative oligoclonal bands and polymerase chain reaction for infectious agents (including tuberculosis). Systemic evaluation was negative for cancer, autoimmune diseases (Anti-nuclear antibodies = negative, Anti-neutrophil cytoplasmic antibodies = negative), and infectious diseases. Thoracic computed tomography (CT) showed nonspecific patchy lung infiltrates. Blood laboratory tests were normal (i.e. Erythrocyte sedimentation rate = 2 mm; C-reactive protein = 1,3 mg/L; Leucocytes = 6,880/mm3). Electroencephalogram EEG showed mild diffuse slowing and brief bursts of diffuse delta waves. The patient underwent two brain biopsies that showed tissue rarefaction with vacuolation, very mild inflammatory cell and macrophage infiltrates, absence of demyelination, malignant cells or granulomas, and no signs of tissue infarction or hemorrhagic changes (Fig. 2a to j). Immunostaining showed scarce CD45+ lymphocytes and CD68+ macrophages, without axonal or myelin damage, with few reactive astrocytes and low aquaporin-4 staining in the lesion compared to the normal surrounding areas. Aquaporin-1 staining was also reduced in the lesion, less extensively than aquaporin-4.Fig. 1 Serial brain magnetic resonance imaging studies of a patient with reversible leukoencephalopathy. Brain magnetic resonance imaging (MRI). Initial FLAIR images (a-d) show diffuse symmetrical confluent hyperintensities involving cerebral white matter, extending to the brainstem and cerebellar white matter. Note mass effect evidenced by sulci, fissure and ventricle effacement (more remarkable considering patient’s age - 64 years old). Corresponding white matter MR spectroscopy (e) (multivoxel, TE = 135 ms) demonstrates no definite metabolic changes. Apparent diffusion coefficients (ADC) map (f) demonstrates diffusion facilitation, signaling vasogenic edema. There was no contrast enhancement (not shown) or significant changes appreciated in color maps proportional to relative cerebral blood volume (rCBV) (g) obtained from a dynamic susceptibility contrast (DSC) perfusion (T2*) study. Color maps proportional to wash in rate (h) obtained from a dynamic contrast-enhanced (DCE) permeability (T1) sequence were also unremarkable. Images F-H are in the same level as D. After treatment for atypical mycobacteriosis, white matter changes disappeared, as shown in (FLAIR) images (i-l) obtained two years after the initial exam (arrows in J and L point to biopsy sites, partially characterized in these images)\n\nFig. 2 Brain biopsy results of a patient with reversible leukoencephalopathy. a to j: Brain biopsy results of the patient with reversible leukoencephalopathy prior to atypical mycobacteria treatment shows (a) mild tissue rarefaction with vacuolation, very sparse perivascular inflammatory infiltrates, and (b) no evidence of demyelination. c–d Presence of relatively few glial fibrillary acidic protein (GFAP) positive astrocytes with reduced aquaporin-4 expression in the lesion compared to the surrounding area. Scale bar = 100 μm. High magnification (400x) on D shows aquaporin-4 on the membrane of reactive astrocytes. Scale bar = 10 μm. e Aquaporin-1 expression is also reduced in the lesion, but in less extensively than aquaporin-4. f–g Myelin sheath is preserved with no loss of myelin basic protein (MBP) and myelin associated glycoprotein (MAG). h No signs of neuronal or axonal damage. i–j Few lymphocytes (CD45+) and macrophages (CD68+) are found in the perivascular space, while immunoglobulin and complement C9neo deposition are absent (not shown). Scale bar = 50 μm. (Magnification a–d = 100x; e–j = 200x)\n\n\n\nThe patient was treated initially with intravenous methylprednisolone (1 g/day for three days), followed by oral dexamethasone (10 mg/day) for six months. Clinical and neurologic status and brain MRI remained unchanged. Activities of daily living were impaired, with a Functional Activity Questionnaire (FAQ) score of 25 and MMSE score of 18. Whole body positron emission tomography-computed tomography obtained at this point revealed a hypermetabolic right pulmonary mass. Lesion histology showed granulomas containing Mycobacterium abscessus. The patient was treated with levofloxacin, clarithromycin and amycacin. Steroids were tapered and discontinued. A year later, cognitive functions and functional status were improved (MMSE = 21; FAQ score = 10) (Table 1), and brain MRI disclosed remarkable resolution of white matter changes (Fig. 1i–l).\n\nConclusions\nThis report illustrates a case of leukoencephalopathy associated with atypical pulmonary mycobacteriosis. Although we cannot establish a cause-effect relationship of atypical mycobacteriosis and leukoencephalopathy, lack of central nervous system (CNS) granulomas and caseous necrosis, lack neurological worsening following steroid therapy, and improvement after antimycobacterial treatment suggest a remote effect of the lung infection, causing the CNS disorder.\n\nInitial chest CT had initially shown nonspecific patchy lung infiltrates, that could, retrospectively, indicate early stage atypical mycobacterial infection. Additionally, the patient presented remarkable, albeit partial, neurological improvement after antimycobacterial treatment. There was no response to steroid therapy, brain pathology studies did not disclose inflammatory activity, and there was absence of intra-thecal antibody production, rendering the possibility of an adaptative immune mechanism (i.e. antibody or cell-mediated immune responses) extremely unlikely. Steroid therapy may have contributed to worsening of the mycobacterial lung infection.\n\nMycobacteria are known to be highly immunogenic: mycobacteria containing compounds are used in mouse models of ADEM and Multiple Sclerosis, through activation of adaptative immunity [17, 18]. Mycobacteria also activate the innate immune system, with production of cytokines and inflammation mediators, such as nitric oxide [19].\n\nMechanism of brain involvement in this case can be inferred from imaging and pathology findings of tissue edema with scarce reactive astrocytes, and reduced aquaporin-4 and aquaporin-1 expression in the lesion, compared to surrounding areas. Considering the lack of evidence of adaptative immune response in the brain, we speculate that activation of an innate-immune response in the lung either by the mycobacteria or through a host mediated response may have exerted a remote effect on aquaporin expression in the brain, leading to interstitial white matter edema. Alternatively, but less likely, antimycobacterial agents may have exerted a direct action reverting white matter lesions [20].\n\nFew studies have evaluated pathological findings in reversible encephalopathies [1, 2, 8, 21], and some studies suggest the pathogenic role of cellular channel dysfunction. Reversible leukoencephalopathy has been described in few anti-aquaporin-4 antibody positive neuromyelitis optica (NMO) cases following immunotherapeutic interventions [3]. Lesion reversibility in these cases suggests that immune-mediated tissue destruction associated with blood–brain barrier (BBB) disruption may not be the main underlying mechanism.\n\nIt is conceivable that vasogenic edema noted on diffusion-weighted MRI sequences in reversible leukoencephalopathy cases represents parenchymal excess water content, caused by impaired water influx control, independent from BBB disruption. In our case, water influx control was probably impaired due to astrocyte aquaporin dysfunction, in a mechanism akin to that hypothesized in brain edema associated with NMO [3]. Additionally, experimentally induced acute hypertension in rabbits led to exogenous markers leakage in arterioles and capillaries through channels (often sigmoid-shaped) and cytoplasm and by transendothelial pinocytosis, causing brain-barrier disruption and edema [22]. These findings suggest impaired water channel function as a possible mechanism underlying reversible leukoencephalopathy.\n\nWe are not aware of previous non-demyelinating reversible leukoencephalopathy cases that improved after atypical mycobacteriosis treatment. We found vacuolated white matter lesions with paucity of reactive astrogliosis and decreased aquaporin water-channel expression. A causal relationship between mycobacteriosis and interstitial edema remains speculative. Alternatively, unexpected drug effects may have contributed to brain changes resolution. Elucidating pathogenic mechanisms underlying reversible leukoencephalopathies may lead to improved therapeutic strategies to treat this condition.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nADEMAcute disseminated encephalomyelitis\n\nADCApparent diffusion coefficients\n\nBBBBlood–brain barrier\n\nCNSCentral nervous system\n\nCTComputed tomography\n\nDCEDynamic contrast-enhanced\n\nDSCDynamic susceptibility contrast\n\nFLAIRFluid attenuation inversion recovery\n\nFAQFunctional Activity Questionnaire\n\nMRIMagnetic resonance imaging\n\nMMSEMini-Mental Status Exam\n\nNMONeuromyelitis optica\n\nPRESPosterior reversible encephalopathy syndrome\n\nrCBVRelative cerebral blood volume\n\nCompeting interests\n\n\nDr. Oliveira has no conflicts of interest to disclose. Dr. Castro has no conflicts of interest to disclose. Dr. Sato is an associated editor of the Arquivos de Neuropsiquiatria (official journal of the Brazilian Academy of Neurology), receives scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, has received research support from Ichiro Kanehara Foundation (2011), and speaker honorarium from Novartis. Dr. Soares-Neto has no conflicts of interest to disclose. Dr. Lucato has no conflicts of interest to disclose. Dr. Callegaro has no conflicts of interest to disclose. Dr. Medeiros has no conflicts of interest to disclose. Prof. Misu has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Prof. Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010–2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Prof. Nitrini has no conflicts of interest to disclose.\n\nAuthors’ contributions\n\nMCBO = conception and study design, data analysis and drafting the manuscript; LHMC = study design, data analysis, and drafting the manuscript; DKS = study conception, data analysis and drafting the manuscript; HRSN = data analysis, and drafting the manuscript; LTL = data analysis and review of the manuscript; DC = conception of the study, data analysis and review of the manuscript; RSSM = data analysis and review of the manuscript; TM = design of the study, data analysis, and drafting the manuscript; KF = study conception, data analysis and review of the manuscript; RN = study conception, data analysis and review of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was partially supported by KAKENHI (22229008) of The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and by the Health and Labor Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labor and Welfare of Japan. The funding sources had no role in the design, collection, analysis, or interpretation of the study, nor in the writing of the article or decision to submit.\n==== Refs\nReferences\n1. Hinchey J Chaves C Appignani B Breen J Pao L Wang A A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 10.1056/NEJM199602223340803 8559202 \n2. Lee VH Wijdicks EM Manno EM Rabinstein AA Clinical spectrum of reversible posterior leukoencephalopathy syndrome Arch Neurol 2008 65 205 210 18268188 \n3. Magaña SM Matiello M Pittock SJ McKeon A Lennon VA Rabinstein AA Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders Neurology 2009 72 8 712 717 10.1212/01.wnl.0000343001.36493.ae 19237699 \n4. Mak A Chan BP Yeh IB Ho RC Boey ML Feng PH Neuropsychiatric lupus and reversible posterior leucoencephalopathy syndrome: a challenging clinical dilemma Rheumatology 2008 47 256 262 10.1093/rheumatology/kem319 18084001 \n5. Bartynski WS Boardman JF Zeigler ZR Shadduck RK Lister J Posterior reversible encephalopathy syndrome in infection, sepsis, and shock AJNR Am J Neuroradiol 2006 27 2179 2190 17110690 \n6. Guerriero S, Ciraci L, Centoducati T, Pignatelli F, Lamargese V, Salvati A, et al. Bilateral Visual Loss as Presenting Symptom of Posterior Reversible Encephalopathy Syndrome in a Patient with HIV/Tuberculosis Coinfection: A Case Report. Case Rep Ophthalmol Med. 2012; doi: 10.1155/2012/850176\n7. Viehman JA Khalil D Barhoma C Hanna RM Mycobacterium avium-intracellulare otomastoiditis in a young AIDS patient: case report and review of the literature Hiv/Aids 2013 5 61 66 23459156 \n8. Feske SK Posterior reversible encephalopathy syndrome: a review Semin Neurol 2011 31 202 215 10.1055/s-0031-1277990 21590625 \n9. Dastur DK Udani PM The pathology and pathogenesis of tuberculous encephalopathy Acta Neuropathol 1966 6 311 326 10.1007/BF00688161 5297864 \n10. Dastur DK The pathology and pathogenesis of tuberculous encephalopathy and myeloradiculopathy: a comparison with allergic encephalomyelitis Childs Nerv Syst 1986 2 13 19 10.1007/BF00274027 3731158 \n11. Udani PM Dastur DK Tuberculous encephalopathy with and without meningitis. Clinical features and pathological correlations J Neurol Sci 1970 10 541 561 10.1016/0022-510X(70)90187-5 5422557 \n12. Lammie GA Hewlett RH Schoeman JF Donald PR Tuberculous encephalopathy: a reappraisal Acta Neuropathol 2007 113 3 227 34 10.1007/s00401-006-0172-7 17171342 \n13. Kim HJ Shim KW Lee MK Park MS Kim SH Kim EY Tuberculous encephalopathy without meningitis: pathology and brain MRI findings Eur Neurol 2011 65 3 156 9 10.1159/000324170 21372574 \n14. Char G Morgan OS Tuberculous encephalopathy. A rare complication of pulmonary tuberculosis West Indian Med J 2000 49 1 70 2 10786460 \n15. Chetty KG Kim RC Mahutte CK Acute hemorrhagic leukoencephalitis during treatment for disseminated tuberculosis in a patient with AIDS Int J Tuberc Lung Dis 1997 1 6 579 81 9487459 \n16. Okada H Yoshioka K Acute Disseminated Encephalomyelitis Associated with Meningitis due to Mycobacterium intracellulare Inter Med 2010 49 2113 2116 10.2169/internalmedicine.49.3323 \n17. Wolf NA Amouzegar TK Swanborg RH Synergistic interaction between Toll-like receptor agonists is required for induction of experimental autoimmune encephalomyelitis in Lewis rats J Neuroimmunol 2007 185 1–2 115 22 10.1016/j.jneuroim.2007.02.001 17341432 \n18. Zorzella-Pezavento SF Guerino CP Chiuso-Minicucci F França TG Ishikawa LL Masson AP BCG and BCG/DNAhsp65 Vaccinations Promote Protective Effects without Deleterious Consequences for Experimental Autoimmune Encephalomyelitis Clin Dev Immunol 2013 2013 721383 10.1155/2013/721383 24288555 \n19. Lee J Sandor M Heninger E Fabry Z Mycobacteria-induced suppression of autoimmunity in the central nervous system J Neuroimmune Pharmacol 2010 5 2 210 9 10.1007/s11481-010-9199-6 20333556 \n20. Dalhoff A Shalit I Immunomodulatory effects of quinolones Lancet Infect Dis 2003 3 359 371 10.1016/S1473-3099(03)00658-3 12781508 \n21. Chester EM Agamanolis DP Banker BQ Victor M Hypertensive encephalopathy: a clinicopathologic study of 20 cases Neurology 1978 28 928 939 10.1212/WNL.28.9.928 567764 \n22. Hansson HA Johansson B Blomstrand C Ultrastructural studies on cerebrovascular permeability in acute hypertension Acta Neuropathol 1975 32 187 198 10.1007/BF00696568 1180001\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "15()", "journal": "BMC neurology", "keywords": null, "medline_ta": "BMC Neurol", "mesh_terms": "D000900:Anti-Bacterial Agents; D003072:Cognition Disorders; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies; D008171:Lung Diseases; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D066127:White Matter", "nlm_unique_id": "100968555", "other_id": null, "pages": "159", "pmc": null, "pmid": "26329680", "pubdate": "2015-09-02", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "23243537;24288555;21590625;5422557;17171342;20930438;12781508;19237699;567764;5297864;1180001;9487459;23459156;10786460;17110690;18084001;3731158;21372574;18268188;20333556;8559202;17341432", "title": "Leukoencephalopathy resolution after atypical mycobacterial treatment: a case report.", "title_normalized": "leukoencephalopathy resolution after atypical mycobacterial treatment a case report" }	[ { "companynumb": "BR-PFIZER INC-2015310153", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "011856", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/DAY FOR THREE DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE SODIUM SUCCINATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/DAY FOR SIX MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atypical mycobacterial infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OLIVEIRA, M.. 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LEUKOENCEPHALOPATHY RESOLUTION AFTER ATYPICAL MYCOBACTERIAL TREATMENT: A CASE REPORT. BMC NEUROLOGY. 2015;15(1):.", "literaturereference_normalized": "leukoencephalopathy resolution after atypical mycobacterial treatment a case report", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20150923", "receivedate": "20150923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11543440, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "We report here 2 pediatric cases of multidrug-resistant (MDR) tuberculosis (TB) that were observed in Italy. Both families came from an Eastern European country, which is notably an area with a high prevalence of MDR TB. An increase of new cases of MDR TB in developed countries is expected over the next years because of migratory flow, and specific measures and strategies need to be taken to prevent the propagation and dissemination of MDR TB. An efficacious treatment including linezolid and moxifloxacin was administered for 13 months in 1 case. No adverse reactions were detected during close child monitoring. Linezolid and newer fluoroquinolones such as moxifloxacin have been reported to be effective for MDR-TB treatment in adults. On the contrary, there is limited available evidence regarding the effectiveness and safety of these drugs in infants and children with MDR TB. The use of second-line drugs not approved for use in children may be necessary to treat a life-threatening disease such as MDR TB, but it requires careful monitoring to quickly recognize the occurrence of dose- and duration-dependent adverse drug reactions.", "affiliations": "Clinic of Infectious Diseases, Department of Pediatrics, University of Turin, Regina Margherita Children's Hospital, Turin, Italy. [email protected]", "authors": "Pinon\|Michele\|M\|;Scolfaro\|Carlo\|C\|;Bignamini\|Elisabetta\|E\|;Cordola\|Giorgio\|G\|;Esposito\|Irene\|I\|;Milano\|Rosangela\|R\|;Mignone\|Federica\|F\|;Bertaina\|Chiara\|C\|;Tovo\|Pier-Angelo\|PA\|", "chemical_list": "D000081:Acetamides; D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D023303:Oxazolidinones; D011804:Quinolines; D000069349:Linezolid; D000077266:Moxifloxacin", "country": "United States", "delete": false, "doi": "10.1542/peds.2009-2172", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "126(5)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000081:Acetamides; D000995:Antitubercular Agents; D001372:Aza Compounds; D002675:Child, Preschool; D054242:Emigrants and Immigrants; D005260:Female; D024841:Fluoroquinolones; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007558:Italy; D000069349:Linezolid; D008297:Male; D008826:Microbial Sensitivity Tests; D008966:Moldova; D000077266:Moxifloxacin; D023303:Oxazolidinones; D011804:Quinolines; D012383:Romania; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant", "nlm_unique_id": "0376422", "other_id": null, "pages": "e1253-6", "pmc": null, "pmid": "20974784", "pubdate": "2010-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Two pediatric cases of multidrug-resistant tuberculosis treated with linezolid and moxifloxacin.", "title_normalized": "two pediatric cases of multidrug resistant tuberculosis treated with linezolid and moxifloxacin" }	[ { "companynumb": "ZA-ALKEM LABORATORIES LIMITED-ZA-ALKEM-2018-03711", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KANAMYCIN\\KANAMYCIN A SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, 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{ "abstract": "We report a case of fatal chronic Candida dubliniensis meningitis complicated by severe hydrocephalus secondary to liver transplantation, in which diagnosis was considerably delayed.", "affiliations": "Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.;Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.", "authors": "Gheshlaghi\|Mariam\|M\|;Helweg-Larsen\|Jannik\|J\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2019.12.009", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30111-310.1016/j.mmcr.2019.12.009Case ReportFatal chronic meningitis caused by Candida dubliniensis after liver transplantation Gheshlaghi Mariam Helweg-Larsen Jannik [email protected]∗Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark∗ Corresponding author. [email protected] 12 2019 3 2020 17 12 2019 27 22 24 26 10 2019 5 12 2019 16 12 2019 © 2019 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of fatal chronic Candida dubliniensis meningitis complicated by severe hydrocephalus secondary to liver transplantation, in which diagnosis was considerably delayed.\n\nKeywords\nCandida dubliniensis meningitisChronic meningitisLiver transplantationInvasive candidiasis\n==== Body\n1 Introduction\nChronic meningitis caused by candida is rare and often difficult to diagnose. Candida dubliniensis meningitis has only been described in very few cases. We report a case of fatal chronic C. dubliniensis meningitis complicated by hydrocephalus secondary to liver transplantation, in which diagnosis was considerably delayed. To our knowledge, this is the seventh reported case of C. dubliniensis meningitis [[1], [2], [3], [4], [5], [6]].\n\n1.1 Case\nThree months after liver transplantation, a 32-year-old male was admitted (day 0) because of four weeks of headache, nausea and intermittent fever. His previous medical history included ulcerative colitis, diabetes and progressive liver failure secondary to primary sclerosing cholangitis with autoimmune hepatitis. After liver transplantation, recovery was delayed because of biliary strictures and cholangitis from which he recovered without signs of rejection or invasive candidiasis. Before admission, standard dosages of tacrolimus, mycophenolate mofetil and prednisone were used for the prevention of rejection. No antifungal prophylaxis was given.\n\nOn admission, his headache was severe, but neurological examination was unremarkable. Lumbar puncture revealed a cerebrospinal fluid (CSF) white cell count of 438 × 106 with 55% neutrophils, protein 1.1 g/L and glucose 3.0 mmol/L (Table 1). Microscopy, extended CSF cultures and broad-range PCR were negative for bacteria, vira and fungi. CT and MRI of the brain as well as CSF opening pressure were normal. Empirical treatment with meropenem, ciprofloxacin and acyclovir were initiated without improvement. Subsequently, lumbar punctures were repeated, which demonstrated decreasing pleocytosis and increasing CSF protein, but remained negative by culture and PCR. Repeated MRI and CT was also unremarkable. CSF opening pressure was not at this time measured. Initially, the severity headache was fluctuating, but worsened at day +21 with development of hydrocephalus, requiring external ventricular drainage (EVD). At day +28, a fourth CSF culture finally grew C. dubliniensis, which at this time also was detected by 18s rRNA PCR of the CSF. Species identification was done at the National Reference Unit of Mycology, Statens Serum Institut, as previously reported [7]. Beta-D-glucan testing was not performed.Table 1 Cerebrospinal fluid findings.\n\nTable 1Week of admission\tNucleated cells (x 10 6/l)\tNeutrophils (x 106/l)\tProtein (g/dl)\tMicrobiology\t\n1\t438\t243\t1.05\tNegative\t\n2\t269\t101\t1.21\tNegative\t\n3\t211\t99\t1.62\tNegative\t\n4\t91\t43\t0.66\tCulture/PCR 18s rRNA d\t\n5\t244\t217\t0.77\ta Culture d\t\n6\t119\t96\t0,86\t–\t\n7\t45\t22\t0.52\t–\t\n8\t16\t11\t0.26\t–\t\n9\t20\t11\t0.23\t–\t\n10\t73\t42\t>6\t–\t\n11\t49\t37\t2\t–\t\n12\t292\t173\t>6\t-b\t\n13\t–\t–\t–\t–\t\n14\t–\t–\t–\t–\t\n15\t66\t24\t>6\t–\t\n16\t20\t13\t0.19\tc\t\n17\t67\t35\t0.45\t–\t\n18\t32\t12\t0.58\t\t\nCandida dubliniensis, sensitive to Voriconazol (MIC: 0.008 mg/L), Amphotericin B (MIC: 0.032 mg/L), Fluconazol (MIC: 0.125 mg/L).The majority of CSF samples after week 4 were obtained from external ventricular drainage.\n\na After 3 days of treatment.\n\nb PCR negative.\n\nc A few yeasts by microscopy. CSF culture negative, Candida mannan antigen in CSF >500 pg/ml. PCR not done.\n\nd Positive. - Culture negative.\n\n\n\nTreatment with ambisome and flucytosine was initiated and the EVD drain was changed with addition of intrathecal amphotericin B. Because of persistent side-effects, flucytosine was replaced with high dose fluconazole. Repeated attempts of EVD weaning failed because of persisting hydrocephalus, which lead to placement of a ventriculoperitoneal (VP) shunt. At this time, the patient's condition improved somewhat. Repeated CSF cultures were negative, but CSF inflammation persisted (Table 1). At day +70, MRI demonstrated subarachnoidal leptomeningeal enhancement and discrete signal changes in the medulla oblongata. Amphotericin B was discontinued after +84 days of treatment and fluconazole 800 mg x1 was continued. During the next weeks, his clinical condition deteriorated again with MRI showing severe enhancement and oedema at the cisterna magna with stenosis of the aqueduct. Treatment with Amphotericin B and flucytosine was restarted, the VP shunt was removed, and intrathecal caspofungin was added. Empiric antibiotics for suspected EVD associated ventriculitis was also given.\n\nDespite aggressive antifungal therapy, his condition deteriorated slowly with increasing double vision, memory loss and tremors. By MRI increased blockage of the foramen Monroe and oedema of the medulla oblongata was found. A few yeasts and an elevated Candida mannan antigen level were at this time detected in the CSF, but cultures remained negative. Further reduction of the immunosuppressive therapy was attempted, however, acute on chronic liver graft rejection developed and the patient died shortly after. Investigations (without DNA sequencing) for primary immunodeficiencies were negative.\n\n2 Discussion\nCandida is as rare cause of CNS infection among immunocompromised patients and associated with mortality rates over 50% [8,9]. Usually, candida meningitis is caused by C.albicans, however cases of C. dubliniensis have been reported after 2008, in which the first case was described [1]. C. dubliniensis is closely related to C. albicans, which it resembles by the ability to produce hyphae and chlamydospores. Infection models have suggested that C. dubliniensis is less pathogenic than C. albicans [10]. However, invasive candidiasis (IC) caused by non-albicans species are increasing [11,12]. A recent Danish nationwide study observed a doubling in the incidence of C. dubliniensis fungemia from 2012 to 2015 [12]. Previous reports of C. dubliniensis meningitis have been related to heart and lung transplantation [1,4], IVDU [5,6], CARD 9 immunodeficiency [3] and cirrhosis [2]. In two of these cases, relapse of C. dubliniensis meningitis was observed after 8 week and 6 months of initial therapy, respectively.\n\nThe diagnosis of candida as a cause of chronic meningitis is often challenging. In most cases, initial CSF findings are pleocytosis with granulocyte predominance and diagnosis may be delayed due to negative CSF culture. In the present case, several repeated CSF cultures and PCR were negative before the final verification of C.dubliniensis. Similar difficulties have been described previously. In a case of C. albicans meningitis secondary to liver transplantation reported by Ralph et al., biopsy from the brain and meninges and four repeated CSF cultures were culture and microscopy negative before CSF grew C. albicans [13]. More recently, Wilson et al. reported a 26-year-old IVDU with diffuse brainstem and spinal cord leptomeningitis in which C. dubliniensis was first established by metagenomic next-generation sequencing of CSF after 6 months of extensive negative diagnostic studies including repeated cultures, CSF 18s/6s rRNA PCR and meningeal biopsies [5].\n\nDespite development of severe meningitis and hydrocephalus, initial repeated MRI did not show meningeal inflammation or raised ICP, similar to other case reports [13]. The present case of candida meningitis has several clinical features similar to cryptococcal meningitis in which initial MRI and CSF opening pressure may fail to demonstrate meningitis with raised CNS ICP, and in which hydrocephalus is associated with high mortality [[14], [15], [16], [17]].\n\nThe optimal treatment of candida meningitis is not established, but usually requires intensive prolonged treatment with combination fungicidal treatment such as amphotericin B and flucytosine. In this case, a combination of complicated hydrocephalus, antifungal treatment toxicity and liver failure was fatal despite negative CSF cultures during high-dose systemic combination and intra-thecal antifungal therapy.\n\nThe reason for candida meningitis in the present case is unclear. Candida meningitis is caused by hematogenous spread with secondary cross of the blood brain barrier after which, Candida is able to form biofilms that evade the CNS microglial defense [18]. However, in several case reports, preceding candidemia/IC were not observed. Although liver transplantation is associated with higher risk of invasive fungal infections compared to other SOT, our patient was young, had no previous evidence of IC and did only receive routine immunosuppressive treatment [19,20] In theory, the patient may have had an innate immunodeficiency in keeping with his history of autoimmune hepatitis and colitis ulcerosa, however permission to DNA exome sequencing was not granted.\n\nC. dubliniensis as a cause of chronic meningitis remains rare but appears to be increasing in parallel with the increase in non-albicans invasive candidiasis. Diagnosis and management remain challenging, particularly in case of complicated hydrocephalus, which in our patient was fatal. In culture negative chronic meningitis, candida should be considered and may require repeated CSF investigations. Recent publications have suggested that molecular methods such as metagenomic next-generation sequencing may facilitate early diagnosis [5], however the diagnostic performance of DNA based CSF methods are not established, as shown in our case, in which initial PCR analysis were negative and it remains important to obtain large CSF volumes for specific fungal culturing.\n\nDeclaration of competing interest\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 van Hal S.J. Stark D. Harkness J. Marriott D. Candida dubliniensis meningitis as delayed sequela of treated C. dubliniensis fungemia Emerg. Infect. Dis. 14 2008 327 329 18258133 \n2 Yamahiro A. Lau K.H.V. Peaper D.R. Villanueva M. Meningitis caused by Candida dubliniensis in a patient with cirrhosis: a case report and review of the literature Mycopathologia 181 2016 589 593 27038312 \n3 Drewniak A. Gazendam R.P. Tool A.T.J. van Houdt M. Jansen M.H. van Hamme J.L. van Leeuwen E.M.M. Roos D. Scalais E. de Beaufort C. Janssen H. van den Berg T.K. Kuijpers T.W. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency Blood 121 2013 2385 2392 23335372 \n4 Herrera S. Pavone P. Kumar D. Singer L. Humar A. Chaparro C. Keshavjee S. Husain S. Rotstein C. Chronic Candida dubliniensis meningitis in a lung transplant recipient Med. Mycol. Case Rep. 24 2019 41 43 30976504 \n5 Wilson M.R. O'Donovan B.D. Gelfand J.M. Sample H.A. Chow F.C. Betjemann J.P. Shah M.P. Richie M.B. Gorman M.P. Hajj-Ali R.A. Calabrese L.H. Zorn K.C. Chow E.D. Greenlee J.E. Blum J.H. Green G. Khan L.M. Banerji D. Langelier C. Bryson-Cahn C. Harrington W. Lingappa J.R. Shanbhag N.M. Green A.J. Brew B.J. Soldatos A. Strnad L. Doernberg S.B. Jay C.A. Douglas V. Josephson S.A. DeRisi J.L. Chronic meningitis investigated via metagenomic next-generation sequencing JAMA Neurol. 75 2018 947 955 29710329 \n6 Andrew N.H. Ruberu R.P. Gabb G. The first documented case of Candida dubliniensis leptomeningeal disease in an immunocompetent host BMJ Case Rep. 2011 4 7 \n7 Arendrup M.C. Dzajic E. Jensen R.H. Johansen H.K. Kjældgaard P. Knudsen J.D. Kristensen L. Leitz C. Lemming L.E. Nielsen L. Olesen B. Rosenvinge F.S. Røder B.L. Schønheyder H.C. Epidemiological changes with potential implication for antifungal prescription recommendations for fungaemia: data from a nationwide fungaemia surveillance programme Clin. Microbiol. Infect. 19 2013 \n8 Voice R.A. Bradley S.F. Sangeorzan J.A. Kauffman C.A. Chronic candidal meningitis: an uncommon manifestation of candidiasis Clin. Infect. Dis. 19 1994 60 66 7948559 \n9 Góralska K. Blaszkowska J. Dzikowiec M. Neuroinfections caused by fungi Infection 46 2018 443 459 29785613 \n10 Moran G.P. Coleman D.C. Sullivan D.J. Candida albicans versus Candida dubliniensis: why Is C. albicans more pathogenic? Internet J. Microbiol. 2012 2012 \n11 Khan Z. Ahmad S. Joseph L. Chandy R. Candida dubliniensis: an appraisal of its clinical significance as a bloodstream pathogen PLoS One 7 2012 e32952 \n12 Astvad K.M.T. Johansen H.K. Røder B.L. Rosenvinge F.S. Knudsen J.D. Lemming L. Schønheyder H.C. Hare R.K. Kristensen L. Nielsen L. Gertsen J.B. Dzajic E. Pedersen M. Østergård C. Olesen B. Søndergaard T.S. Arendrup M.C. Update from a 12-year nationwide fungemia surveillance: increasing intrinsic and acquired resistance causes concern J. Clin. Microbiol. 56 2018 1 15 \n13 Ralph E.D. Hussain Z. Chronic meningitis caused by Candida albicans in a liver transplant recipient: usefulness of the polymerase chain reaction for diagnosis and for monitoring treatment Clin. Infect. Dis. 23 1996 191 192 8816159 \n14 Sarkis R.A. Mays M. Isada C. Ahmed M. 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Epidemiology of invasive fungal infections after liver transplantation and the risk factors of late-onset invasive aspergillosis J. Infect. Chemother. 22 2016 84 89 26683245 \n20 Pappas P.G. Alexander B.D. Andes D.R. Hadley S. a Kauffman C. Freifeld A. Anaissie E.J. Brumble L.M. Herwaldt L. Ito J. Kontoyiannis D.P. Lyon G.M. a Marr K. a Morrison V. Park B.J. Patterson T.F. Perl T.M. a Oster R. Schuster M.G. Walker R. Walsh T.J. a Wannemuehler K. Chiller T.M. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clin. Infect. Dis. 50 2010 1101 1111 20218876\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "27()", "journal": "Medical mycology case reports", "keywords": "Candida dubliniensis meningitis; Chronic meningitis; Invasive candidiasis; Liver transplantation", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "22-24", "pmc": null, "pmid": "31890490", "pubdate": "2020-03", "publication_types": "D002363:Case Reports", "references": "25607331;7948559;26683245;22396802;23607326;18258133;26517766;27886201;30976504;23335372;20218876;29212705;8816159;27038312;29785613;25444972;29710329;22687683;21904553;27858519", "title": "Fatal chronic meningitis caused by Candida dubliniensis after liver transplantation.", "title_normalized": "fatal chronic meningitis caused by candida dubliniensis after liver transplantation" }	[ { "companynumb": "DK-MYLANLABS-2020M1021227", "fulfillexpeditecriteria": "1", "occurcountry": "DK", 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCYTOSINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CASPOFUNGIN" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CASPOFUNGIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (EMPIRICAL TREATMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (EMPIRICAL TREATMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMBISOME" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (STANDARD DOSAGES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "GHESHLAGHI, M.. FATAL CHRONIC MENINGITIS CAUSED BY CANDIDA DUBLINIENSIS AFTER LIVER TRANSPLANTATION.. MEDICAL MYCOLOGY CASE REPORTS. 2020?27:10.1016/J.MMCR.2019.12.009", "literaturereference_normalized": "fatal chronic meningitis caused by candida dubliniensis after liver transplantation", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20200121", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17268686, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "DK-TEVA-2020-DK-1171197", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Aqueductal stenosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Amnesia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis candida", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "GHESHLAGHI M, HELWEG-LARSEN J. FATAL CHRONIC MENINGITIS CAUSED BY CANDIDA DUBLINIENSIS AFTER LIVER TRANSPLANTATION. MED-MYCOL-CASE-REPORTS 2020?27:22-24.", "literaturereference_normalized": "fatal chronic meningitis caused by candida dubliniensis after liver transplantation", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20200122", "receivedate": "20200122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17301139, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "BACKGROUND\nClinical trials evaluating the efficacy of dabigatran followed a very strict protocol, which included close monitoring and follow-up. Patients followed in this controlled environment had an average medication possession ratio (MPR) greater than 0.95. However, very few studies have evaluated patient adherence to dabigatran in a real-world setting. Other studies of chronic medications indicate patients are not reliably adherent to twice daily regimens. Adherence to therapy is particularly important for direct thrombin inhibitors because there may be a risk of increased thromboembolic events associated with poor adherence to these agents.\n\n\nOBJECTIVE\nTo identify the MPR for patients prescribed dabigatran at a large academic medical center and affiliated clinics.\n\n\nMETHODS\nThis retrospective descriptive study evaluated the MPR for patients prescribed dabigatran between January 1, 2012, and December 31, 2012. Patients included in this study had to receive dabigatran for a minimum of 3 months, have a primary care physician or cardiologist at the medical center or affiliated clinics, and must not use a mail order pharmacy. Patient MPR was calculated based on prescriptions picked up from the patient.\n\n\nRESULTS\nAfter screening 400 patients, 159 patients met eligibility criteria. The mean MPR for the patients in this study was 0.63. Overall, 43% of the patients had an MPR of less than 0.80, and the mean MPR for this subgroup was 0.39 ± 0.27; 57% of the study population had an MPR of 0.80 or higher, with a mean MPR of 0.94 ± 0.08. There was a significantly higher proportion of men (67.7%, P = 0.0112) and a larger number of \"as needed medications\" prescribed (1.73 vs. 0.86, P = 0.0039) in patients with an MPR less than 0.80. There were 5 patients hospitalized during the study period (3 for bleeding, 1 for confusion, and 1 death not related to dabigatran therapy).\n\n\nCONCLUSIONS\nThe relatively low mean MPR seen in this study may indicate that there is a need for improved anticoagulation services and follow-up for patients taking dabigatran.", "affiliations": "UCSF School of Pharmacy, 521 Parnassus Ave., Box 0622, San Francisco, CA 94143,USA. [email protected].", "authors": "Cutler\|Timothy W\|TW\|;Chuang\|Alan\|A\|;Huynh\|Tony D\|TD\|;Witt\|Robert G\|RG\|;Branch\|Jennifer\|J\|;Pon\|Tiffany\|T\|;White\|Richard\|R\|", "chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran", "country": "United States", "delete": false, "doi": "10.18553/jmcp.2014.20.10.1028", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "20(10)", "journal": "Journal of managed care & specialty pharmacy", "keywords": null, "medline_ta": "J Manag Care Spec Pharm", "mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D012189:Retrospective Studies; D013923:Thromboembolism; D015091:beta-Alanine", "nlm_unique_id": "101644425", "other_id": null, "pages": "1028-34", "pmc": null, "pmid": "25278325", "pubdate": "2014-10", "publication_types": "D016428:Journal Article", "references": null, "title": "A retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center.", "title_normalized": "a retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center" }	[ { "companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-49557GD", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CUTLER T,CHUANG A,HUYNH T,WITT R,BRANCH J,PON T,WHITE R. A RETROSPECTIVE DESCRIPTIVE ANALYSIS OF PATIENT ADHERENCE TO DABIGATRAN AT A LARGE ACADEMIC MEDICAL CENTER. J MANAGED CARE PHARM 2014 OCT;20:10:1028-1034.", "literaturereference_normalized": "a retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20141020", "receivedate": "20141020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10528808, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150528" }, { "companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-49556GD", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematuria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CUTLER T,CHUANG A,HUYNH T,WITT R,BRANCH J,PON T,WHITE R. A RETROSPECTIVE DESCRIPTIVE ANALYSIS OF PATIENT ADHERENCE TO DABIGATRAN AT A LARGE ACADEMIC MEDICAL CENTER. J MANAGED CARE PHARM 2014 OCT;20:10:1028-1034.", "literaturereference_normalized": "a retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20141020", "receivedate": "20141020", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10528810, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150528" } ]
{ "abstract": "If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission.\n\n\n\nTo investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi.\n\n\n\nOpen-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS < 1.6) at week 50.\n\n\n\nEight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308).\n\n\n\nRemission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients.\n\n\n\nRegistered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.", "affiliations": "Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.;Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.;Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam, the Netherlands.;Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, the Netherlands.;Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam, the Netherlands.;Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.;Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. [email protected].", "authors": "de Jong\|Henriëtte M Y\|HMY\|0000-0003-1818-180X;van Mens\|Leonieke J J\|LJJ\|;Nurmohamed\|Michael T\|MT\|;Kok\|Marc R\|MR\|;van Kuijk\|Arno W R\|AWR\|;Baeten\|Dominique L P\|DLP\|;van de Sande\|Marleen G H\|MGH\|", "chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors; C529000:golimumab; D008727:Methotrexate", "country": "England", "delete": false, "doi": "10.1186/s13075-019-1998-4", "fulltext": "\n==== Front\nArthritis Res TherArthritis Res. TherArthritis Research & Therapy1478-63541478-6362BioMed Central London 199810.1186/s13075-019-1998-4Research ArticleSustained remission with methotrexate monotherapy after 22-week induction treatment with TNF-alpha inhibitor and methotrexate in early psoriatic arthritis: an open-label extension of a randomized placebo-controlled trial http://orcid.org/0000-0003-1818-180Xde Jong Henriëtte M. Y. 12van Mens Leonieke J. J. 12Nurmohamed Michael T. 234Kok Marc R. 5van Kuijk Arno W. R. 24Baeten Dominique L. P. 12van de Sande Marleen G. H. [email protected] 121 0000000084992262grid.7177.6Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands 2 0000 0004 0435 165Xgrid.16872.3aAmsterdam Rheumatology & Immunology Center (ARC), Amsterdam, the Netherlands 3 0000 0004 1754 9227grid.12380.38Department of Rheumatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 4 0000 0004 0624 3484grid.418029.6Department of Rheumatology, Reade, Amsterdam, the Netherlands 5 0000 0004 0460 0556grid.416213.3Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, the Netherlands 14 9 2019 14 9 2019 2019 21 20818 6 2019 5 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIf TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission.\n\nObjective\nTo investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi.\n\nMethods\nOpen-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS < 1.6) at week 50.\n\nResults\nEight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308).\n\nConclusions\nRemission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients.\n\nTrial registration\nRegistered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.\n\nKeywords\nEarly psoriatic arthritisRemissionTreatment withdrawalMethotrexateTNF inhibitorhttp://dx.doi.org/10.13039/100009947Merck Sharp and DohmeNAissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nBiologics have drastically changed the field of rheumatology. Whereas they have originally been used to treat patients who were refractory to classical disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX), increasing evidence shows that their use in early disease allows to achieve high remission rates [1–4]). Moreover, it has been postulated that if biologics are initiated in the early stages of disease, during the so-called window of opportunity [5], this could promote an immune reset rather than merely suppression of inflammation and thereby alter the course of the disease and allow for discontinuation of treatment in patients who achieve remission.\n\nMost of the studies exploring these concepts have been conducted in rheumatoid arthritis. It remains unclear to what extent these concepts may also apply to psoriatic arthritis (PsA), a subgroup of spondyloarthritis that can present with skin and nail psoriasis, arthritis, enthesitis, dactylitis, and axial disease [6].\n\nWe recently demonstrated that initiation of tumor necrosis factor alpha inhibition (TNFi) with golimumab in combination with MTX doubled the number of early PsA patients achieving Disease Activity Score (DAS) remission at week 22 in comparison with MTX monotherapy from 42% with MTX alone to 81% with golimumab plus MTX combination therapy [4]. To explore the hypothesis that remission induced by TNFi plus MTX in patients with early psoriatic arthritis can be sustained after withdrawal of TNFi, we conducted an open-label extension study of this trial with patients that were in DAS-CRP remission at week 22 and continued on MTX monotherapy. Disease activity was assessed at weeks 36 and 50.\n\nMethods\nStudy design and patients\nThe original study design and baseline characteristics have been described in detail [4]. In short, 51 patients with psoriatic arthritis (PsA), fulfilling the CASPAR criteria and with active disease (defined as swollen and tender joint count ≥ 3), were included. During the double-blind phase (up to week 22), all patients received methotrexate (MTX) up to 25 mg/week and were randomized to either golimumab 50 mg/month (n = 26) or matched placebo (n = 24). Patients with a status of DAS-CRP remission at week 22, defined by a DAS-CRP score < 1.6, were offered to enter the open-label extension phase up to week 50 on MTX monotherapy. A clinical assessment was done at week 36 and week 50, and an additional visit was done in the case of worsening or recurrence of symptoms. Participants who had loss of remission were withdrawn from the trial. The group that originally used MTX and placebo will further be referred to as the ‘original MTX group’, and the group that used methotrexate and golimumab will further be referred to as the ‘original MTX+TNFi group’.\n\nThis study was conducted at three centres in the Netherlands between September 2013 and September 2017 and was approved by the Medical Ethics Committee of the Academic Medical Centre in Amsterdam. Written informed consent was obtained from each patient before enrolment. The study was conducted in compliance with the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki and is registered at clinicaltrials.gov under NCT01871649.\n\nAssessments\nThe primary efficacy end point of this study was the percentage of patients who sustained a status of DAS-CRP remission [7] (DAS-CRP score < 1.6) at week 50. Secondary efficacy end points included Low Disease Activity (LDA) status (DAS-CRP < 2.4), criteria for Minimal Disease Activity (MDA) [8], and Disease Activity in Psoriatic Arthritis Low Disease Activity (DAPSA-LDA) [9]. Clinical evaluations, patient-reported outcomes, and standard laboratory tests were done at every study visit. Safety end points included adverse events (AEs) and serious AEs (SAEs) and discontinuation or interruption of study treatment.\n\nStatistical analysis\nData are presented as mean (SD) unless indicated otherwise. Differences between both groups were analysed with a chi-square test for categorical data and a Mann-Whitney U test for continuous data. The primary and secondary outcomes were analysed with an intention-to-treat analysis. Patients that discontinued for any reason during the extension study were considered non-responders, as were patients that were in remission at week 22 but did not attend a study visit during the extension study. All statistical tests were two sided, and a p value of < 0.05 was considered statistically significant.\n\nResults\nStudy population and patient disposition\nThe patient disposition and flow chart are summarized in Fig. 1. Ten patients from the original MTX group achieved remission in the first 22 weeks of the study. Of those, 2 were lost to follow-up. Therefore, 8 patients from the original MTX group entered the extension phase, of whom 6 completed week 50. For the original MTX+TNFi group, 21 patients achieved remission in the first 22 weeks of the study. Three were excluded before the start of the extension phase; therefore, 18 patients entered the extension phase, of whom 10 completed week 50.\nFig. 1 The patient disposition and flow chart\n\n\n\nBaseline characteristics of the total study cohort have been described previously [4]. Table 1 shows demographics, disease characteristics, and disease activity measures of the 26 patients (18 from the original MTX+TNFi group and 8 from the original MTX group) continuing in the extension phase for baseline and weeks 22, 36, and 50 (data as observed). Demographics did not differ between both groups. At baseline VAS, patient pain was lower in the original MTX group compared to that in the original MTX+TNFi group (p = 0.011), as was the BASDAI (p = 0.047). At week 22, PASI score was significantly higher in the original MTX group (p = 0.001). At weeks 36 and 50, there were no differences between both groups. The overall mean (SD) dosage of methotrexate in the extension phase was comparable in both groups: 22.5 (4.9) mg/week in the original MTX group and 20.9 (6.2) mg/week in the original MTX+TNFi group (non-significant).\nTable 1 Demographics, characteristics, and disease activity measures as observed on patients who entered the extension study\n\n\tBaseline\tWeek 22\tWeek 36\tWeek 50\t\nOriginal MTX (n = 8)\tOriginal MTX+TNFi (n = 18)\t\np\n\tOriginal MTX (n = 8)\tOriginal MTX+TNFi (n = 18)\t\np\n\tOriginal MTX (n = 8)\tOriginal MTX+TNFi (n = 16)\t\np\n\tOriginal MTX (n = 6)\tOriginal MTX+TNFi (n = 10)\t\np\n\t\nAge\t46 (13.1)\t48.7 (10)\tNS\t\t\t\t\t\t\t\t\t\t\nGender (male/female)\t7/1\t13/5\tNS\t7/1\t13/5\tNS\t7/1\t13/3\tNS\t5/1\t9/1\tNS\t\nDisease duration < 2 years, n (%)\t5 (62.5)\t14 (77.8)\tNS\t5 (62.5)\t14 (77.8)\tNS\t5 (62.5)\t12 (75)\tNS\t4 (66.7)\t6 (60)\tNS\t\nSJC 66, median (IQR)\t3.5 (3–7.3)\t7 (4–8.3)\tNS\t0.5 (0–2)\t0 (0–1)\tNS\t1 (0.3–2)\t0 (0–1.3)\tNS\t0 (0–1.3)\t0 (0–3.3)\tNS\t\nTJC 68, median (IQR)\t5 (4–13.8)\t10 (4.8–14.3)\tNS\t1 (0.3–3.3)\t0 (0–3.3)\tNS\t1.5 (0.3–2.8)\t1.5 (0–4.5)\tNS\t0 (0–1.5)\t1.5 (0–4.3)\tNS\t\nPASI score, median (IQR)\t2.7 (0.5–6)\t1.9 (0.8–3.8)\tNS\t0.8 (0.4–1.7)\t0\t0.001\t0.5 (0.5–1.8)\t0\tNS\t1 (0.3–1.9)\t0.6 (0–1.3)\tNS\t\nPASI > 2.5, n (%)\t4 (50)\t8 (44.4)\tNS\t1 (12.5)\t0\tNS\t0\t1 (6.3)\tNS\t0\t1 (10)\tNS\t\nPts with enthesitis, n (%)\t0\t2 (11.1)\tNS\t1 (12.5)\t1 (5.6)\tNS\t1 (12.5)\t3 (18.9)\tNS\t0\t1 (10)\tNS\t\nPts with dactylitis, n (%)\t4 (50)\t4 (22.2)\tNS\t1 (12.5)\t0\tNS\t4 (50)\t1 (6.3)\tNS\t1 (16.7)\t1 (10)\tNS\t\nESR (mm/h), median (IQR)\t15.5 (5.5–24.3)\t20.5 (4.3–31.8)\tNS\t7 (3.5–15.8)\t2 (2–18)\tNS\t5.5 (2–10.8)\t5 (2–6.5)\tNS\t5 (2.5–11.5)\t6 (2–12)\tNS\t\nCRP (mg/L), median (IQR)\t9.5 (2.1–14)\t4 (1.3–14.5)\tNS\t3.1 (0.9–15)\t1.1 (0.4–2.9)\tNS\t1.8 (0.7–8)\t1.5 (0.4–4)\tNS\t4.2 (0.9–7.4)\t2 (1–5)\tNS\t\nVAS patient global (mm)\t26.9 (17.8)\t46.3 (24.9)\tNS\t23.4 (25.9)\t17.7 (17.6)\tNS\t18.3 (20.9)\t24.1 (23.8)\tNS\t17.4 (15.2)\t19.8 (20)\tNS\t\nVAS patient pain (mm)\t20 (15.8)\t47.7 (26.1)\t0.011\t8.1 (12.7)\t13.6 (17.5)\tNS\t9.4 (8.7)\t23 (21.6)\tNS\t6.2 (4)\t21 (27.1)\tNS\t\nVAS physician (mm)\t43.1 (14.0)\t45.3 (15.6)\tNS\t12.6 (10.2)\t8.1 (9.3)\tNS\t8.9 (8.1)\t13.8 (19.6)\tNS\t15.6 (12.1)\t13 (17.5)\tNS\t\nBASDAI\t2.4 (1.8)\t4.1 (1.9)\t0.047\t1.5 (1.6)\t1.8 (1.5)\tNS\t1.7 (1.5)\t2 (1.7)\tNS\t1.8 (1.7)\t1.7 (1.4)\tNS\t\n\n\nSafety\nDuring the extension phase, one serious adverse event (SAE) occurred in a patient from the original MTX+TNFi group: a small bowel obstruction with surgical intervention, which was judged unrelated to the study and did not lead to early termination. Eighteen AEs occurred during the extension phase: 9 in the original MTX+TNFi group and 9 in the original MTX group. One patient from the original MTX+TNFi group discontinued after week 40 because of an AE related to the study medication (liver enzymes > 2 times the upper limit of normal).\n\nEfficacy\nSix out of 8 (75%) patients from the original MTX group completed the extension study and maintained DAS remission at week 50. Five out of 6 fulfilled criteria for MDA, and all were in DAPSA-LDA. Two patients had a loss of DAS remission at week 36; 1 had a status of LDA according to the DAS, 1 was in DAPSA-LDA, and none were in MDA.\n\nTen out of 18 patients (56%) from the original MTX+TNFi group completed the extension study and maintained DAS remission at week 50. Six out of 10 fulfilled the criteria for MDA, and 7 out of 10 were in DAPSA-LDA. Of the 8 patients dropping out of this arm of the study, 3 patients discontinued while still in DAS remission but were considered non-responders in the intention-to-treat analysis: 1 discontinued because of an AE (week 40) and 2 discontinued upon their own request (weeks 29 and 36) (Fig. 1). Five patients had a loss of DAS remission (1 at week 29, 3 at week 36, and 1 at week 45); 4/5 patients had a status of LDA according to the DAS, 1/5 was in MDA, and 3/5 in DAPSA-LDA.\n\nIn the intention-to-treat analysis, 6/8 (75%) patients from the original MTX group versus 10/18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission at week 50 (p = 0.347). Considering not only the extension phase but the complete study from baseline to week 50, 6/24 (25%) patients from the original MTX group had a status of DAS-CRP remission at week 50 compared to 10/26 (38%) patients from the original MTX+TNFi group (p = 0.308).\n\nDiscussion\nWe recently reported that initiating combination therapy with MTX+TNFi resulted in doubling the rate of DAS-CRP remission at week 22 (81%) compared to MTX alone in patients (42%) with early psoriatic arthritis (PsA). We hypothesized that achieving remission in this ‘window of opportunity’ would allow to maintain clinical benefit in a substantial number of patients even after stopping the TNFi at week 22. Here we report that 56% of those patients indeed maintained remission up to week 50, whereas 75% of the patient achieving remission at week 22 on MTX monotherapy maintained remission over time. Taking into account the total study population, 38% of the original MTX+TNFi group versus 25% of the original MTX group achieved and maintained remission up to week 50.\n\nA number of important aspects should be taken into consideration when interpreting the data of the present study. First, the number of patients included in the extension phase of the study was small, especially in the original MTX monotherapy group. Second, the study did not assess drug-free remission as all patients were on continuous MTX therapy from baseline to week 50 to reflect standard of care; the study was not designed to assess the real efficacy of MTX. Continuation of MTX in all patients also explains the high maintenance of remission in the original MTX group, as there was no drug withdrawal in this group, only withdrawal of the placebo. Third, the patients and investigators remained blinded during the whole study (up to week 50) for the golimumab versus placebo treatment in the induction phase of the study, but were aware that this initial treatment was withdrawn at week 22. Fourth, we used the most conservative version of the data to do the analyses. Two patients from the original MTX+TNFi group who experienced a flare during the extension phase were actually still in DAS remission, but were nevertheless withdrawn from the study by the study physician because of arthritis in multiple joints not included in the DAS. Although still formally in DAS remission, these patients were considered as having a loss of remission in the analyses. Also patients dropping out for other reasons were considered as non-responders.\n\nDespite these caveats, our findings are concordant with several other studies in PsA and other types of spondyloarthritis [10–12]). Huynh et al. reported that 55.1% of patients with PsA who discontinued TNFi had persistent clinical benefit of TNFi therapy at the last clinical visit. In this study, smoking and higher disease activity at the time of discontinuation were predictors of loss of clinical benefit, but disease duration did not affect the outcome [10].\n\nThe data of the current trial fail to support the hypothesis of immune reset by early TNFi treatment in PsA. In summary, our findings indicate that it is possible to maintain remission on MTX monotherapy in a substantial number of patients with early PsA achieving remission by initial combination treatment with TNFi and methotrexate. However, for how long this remission can be maintained and whether the maintained remission in these patients is due to an immune reset or merely due to suppression of inflammation is not known. Moreover, a fair number of patients in the original MTX+TNFi lost remission after stopping TNFi, which shows that our treatment strategy did not provide the ‘window of opportunity’ to change the disease course in all patients. Whether even earlier initiated (combination) treatment or other targeted treatment could provide a ‘window of opportunity’ with sustained remission in all patients needs further assessment in future treatment strategy trials.\n\nAbbreviations\nTNFiTumour necrosis factor inhibitor\n\nPsAPsoriatic arthritis\n\nMTXMethotrexate\n\nDMARDsDisease-modifying anti-rheumatic drugs\n\nDASDisease Activity Score\n\nCRPC-reactive protein\n\nMDAMinimal Disease Activity\n\nLDALow Disease Activity\n\nDAPSA-LDADisease Activity in Psoriatic Arthritis Low Disease Activity\n\nAEAdverse event\n\nSAESerious adverse event\n\nVASVisual analogue scale\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank all patients that participated in this study and their treating physicians who referred patients. Also we thank Inka Fluri and Maureen Leeuw for their contribution to this study.\n\nAuthors’ contributions\nThe study protocol was designed by DL, LvM, MN, MK, and AvK. LvM, MN, MK, AvK, and MvS recruited and selected patients. Data interpretation was done by HdJ, LvM, DL, and MvS. The manuscript was primarily drafted by HdJ. All authors have read and approved the final version of this manuscript.\n\nFunding\nThis investigator-initiated study was supported by supply of study medication and an unrestricted grant from MSD.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was approved by the Medical Ethics Committee of the Academic Medical Center in Amsterdam. All patients provided written informed consent.\n\nConsent for publication\nNot applicable\n\nCompeting interests\nDB is currently an employee of UCB Pharma. LJJvM and HMdJ declare that they have no competing interest. MGHvdS has been an advisor for Abbvie and Novartis and received research grants from Janssen, Eli Lily, and Novartis. The department of MK is supported by Novartis, Abbvie, Pfizer, Roche, Lilly, and BMS, and MK has been an advisor for Novartis and Abbvie. MTN received research grants, consultation, and/or speaking fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Mundipharma, Novartis, Pfizer, Roche, Sanofi, and UCB Pharma. AWRvK received speaker fees from Celgene, Novartis, Eli Lilly, and Janssen and received research support from MSD and Janssen.\n==== Refs\nReferences\n1. Smolen JS Emery P Fleischmann R Van Vollenhoven RF Pavelka K Durez P Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial Lancet 2014 383 321 332 10.1016/S0140-6736(13)61751-1 24168956 \n2. Atsumi T Tanaka Y Yamatomo K Takeuchi T Yamanaka H Ishiguro N Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial Ann Rheum Dis 2017 76 1348 1356 10.1136/annrheumdis-2016-210246 28153828 \n3. Emery P Bingham CO Burmester GR Bykerk VP Furst DE Mariette X Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study Ann Rheum Dis 2017 76 96 104 10.1136/annrheumdis-2015-209057 27165179 \n4. van Mens Leonieke J J de Jong Henriëtte M Fluri Inka Nurmohamed Michael T van de Sande Marleen G H Kok Marc van Kuijk Arno W R Baeten Dominique Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double-blind, randomised, placebo-controlled trial of golimumab plus methotrexate versus placebo plus methotrexate Annals of the Rheumatic Diseases 2019 78 5 610 616 10.1136/annrheumdis-2018-214746 30808625 \n5. Van Nies JAB Tsonaka R Gaujoux-Viala C Fautrel B Van Der Helm-Van Mil AHM Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts Ann Rheum Dis 2015 74 806 812 10.1136/annrheumdis-2014-206047 25561360 \n6. Van den Bosch F Coates L Clinical management of psoriatic arthritis Lancet 2018 391 2285 2294 10.1016/S0140-6736(18)30949-8 29893227 \n7. van Gestel AM Prevoo MLL van’t Hof MA van Rijswijk MH van de Putte LBA van Riel PLCM Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria Arthritis Rheum 1996 39 34 40 10.1002/art.1780390105 8546736 \n8. Coates LC Fransen J Helliwell PS Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment Ann Rheum Dis 2010 69 48 53 10.1136/ard.2008.102053 19147615 \n9. Schoels M Aletaha D Funovits J Kavanaugh A Baker D Smolen JS Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic arthritis Ann Rheum Dis 2010 69 1441 1447 10.1136/ard.2009.122259 20525844 \n10. Huynh DH Boyd TA Etzel CJ Cox V Kremer J Mease P Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis RMD Open 2017 3 1 4 10.1136/rmdopen-2016-000395 \n11. Carron Philippe Varkas Gaëlle Renson Thomas Colman Roos Elewaut Dirk Van den Bosch Filip High Rate of Drug-Free Remission After Induction Therapy With Golimumab in Early Peripheral Spondyloarthritis Arthritis & Rheumatology 2018 70 11 1769 1777 10.1002/art.40573 29806090 \n12. Landewé R Sieper J Mease P Inman RD Lambert RG Deodhar A Efficacy and safety of continuing versus withdrawing adalimumab therapy in maintaining remission in patients with non-radiographic axial spondyloarthritis (ABILITY-3): a multicentre, randomised, double-blind study Lancet 2018 392 134 144 10.1016/S0140-6736(18)31362-X 29961640\n\n", "fulltext_license": "CC BY", "issn_linking": "1478-6354", "issue": "21(1)", "journal": "Arthritis research & therapy", "keywords": "Early psoriatic arthritis; Methotrexate; Remission; TNF inhibitor; Treatment withdrawal", "medline_ta": "Arthritis Res Ther", "mesh_terms": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors", "nlm_unique_id": "101154438", "other_id": null, "pages": "208", "pmc": null, "pmid": "31521192", "pubdate": "2019-09-14", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "29961640;29893227;8546736;28153828;25561360;20525844;28123783;29806090;24168956;27165179;30808625;19147615", "title": "Sustained remission with methotrexate monotherapy after 22-week induction treatment with TNF-alpha inhibitor and methotrexate in early psoriatic arthritis: an open-label extension of a randomized placebo-controlled trial.", "title_normalized": "sustained remission with methotrexate monotherapy after 22 week induction treatment with tnf alpha inhibitor and methotrexate in early psoriatic arthritis an open label extension of a randomized placebo controlled trial" }	[ { "companynumb": "NL-JNJFOC-20191004919", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GOLIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": "125289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION IN PRE-FILLED PEN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSORIATIC ARTHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMPONI" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE JONG H, VAN MENS L, NURMOHAMED M, KOK M, VAN KUIJK A, BAETEN D, VAN DE SANDE M, DE JONG H. SUSTAINED REMISSION WITH METHOTREXATE MONOTHERAPY AFTER 22-WEEK INDUCTION TREATMENT WITH TNF-ALPHA INHIBITOR AND METHOTREXATE IN EARLY PSORIATIC ARTHRITIS: AN OPEN-LABEL EXTENSION OF A RANDOMIZED PLACEBO-CONTROLLED TRIAL.. ARTHRITIS RES THER. 2019?1-6.", "literaturereference_normalized": "sustained remission with methotrexate monotherapy after 22 week induction treatment with tnf alpha inhibitor and methotrexate in early psoriatic arthritis an open label extension of a randomized placebo controlled trial", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20191011", "receivedate": "20191011", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16906163, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c-Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed.", "affiliations": "Department of Pathology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Experimental Oncology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Department of Pathology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Medical Oncology B Units, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Medical Oncology B Units, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Department of Pathology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;CRO Aviano National Cancer Institute IRCCS, Scientific Directorate, Aviano, PN, Italy. Electronic address: [email protected].;Experimental Oncology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Medical Oncology B Units, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].", "authors": "Canzonieri\|Vincenzo\|V\|;Gasparotto\|Daniela\|D\|;Alessandrini\|Lara\|L\|;Miolo\|Gianmaria\|G\|;Torrisi\|Elena\|E\|;Perin\|Tiziana\|T\|;De Paoli\|Paolo\|P\|;Maestro\|Roberta\|R\|;Buonadonna\|Angela\|A\|", "chemical_list": "D000970:Antineoplastic Agents; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D007633:Keratins", "country": "Germany", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0344-0338", "issue": "212(1)", "journal": "Pathology, research and practice", "keywords": "Aberrant cytokeratin expression; GISTs; Imatinib-resistance; Immunephenotype; Therapy-induced changes", "medline_ta": "Pathol Res Pract", "mesh_terms": "D000970:Antineoplastic Agents; D015820:Cadherins; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D007633:Keratins; D008875:Middle Aged; D010641:Phenotype; D047428:Protein Kinase Inhibitors", "nlm_unique_id": "7806109", "other_id": null, "pages": "63-7", "pmc": null, "pmid": "26616113", "pubdate": "2016-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Morphologic shift associated with aberrant cytokeratin expression in a GIST patient after tyrosine kinase inhibitors therapy. A case report with a brief review of the literature.", "title_normalized": "morphologic shift associated with aberrant cytokeratin expression in a gist patient after tyrosine kinase inhibitors therapy a case report with a brief review of the literature" }	[ { "companynumb": "PHHY2014IT070018", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QD (4 WEEKS ON, 2 WEEKS OFF)", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NILOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NILOTINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, QD", "drugenddate": "201108", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal stromal tumour", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal mass", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neoplasm recurrence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Subileus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201108" } }, "primarysource": { "literaturereference": "ALESSANDRINIA L, CANZONIERIA V, GASPAROTTOB D, MIOLOC G, TORRISI E, PERINA T ET. AL.. MORPHOLOGIC SHIFT ASSOCIATED WITH ABERRANT CYTOKERATIN EXPRESSION IN A GIST PATIENT AFTER TYROSINE KINASE INHIBITORS THERAPY. A CASE REPORT WITH A BRIEF REVIEW OF THE LITERATURE. RESEARCH AND PRACTICE. 2016?212 (1):63-7", "literaturereference_normalized": "morphologic shift associated with aberrant cytokeratin expression in a gist patient after tyrosine kinase inhibitors therapy a case report with a brief review of the literature", "qualification": null, "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160122", "receivedate": "20140613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10235037, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160525" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-112520", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, 4 WEEKS ON, 2 WEEKS OFF", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NILOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NILOTINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078340", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG/ DAY WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078340", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Subileus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANZONIERI V, GASPAROTTO D, ALESSANDRINI L, MIOLO G, TORRISI E, PERIN T, ET AL. MORPHOLOGIC SHIFT ASSOCIATED WITH ABERRANT CYTOKERATIN EXPRESSION IN A GIST PATIENT AFTER TYROSINE KINASE INHIBITORS THERAPY. A CASE REPORT WITH A BRIEF REVIEW OF THE LITERATURE. PATHOL-RES-PRACT. 2016?212 (1):63-67", "literaturereference_normalized": "morphologic shift associated with aberrant cytokeratin expression in a gist patient after tyrosine kinase inhibitors therapy a case report with a brief review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160311", "receivedate": "20160311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12171550, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "To assess clinical outcomes of patients with airway venous malformations treated with percutaneous sclerotherapy (VMPS). We highlight the role of foamed bleomycin as a less inflammatory sclerosant and the importance of collaboration between interventional radiology and otolaryngology-head and neck surgery (OHNS).\n\n\n\nRetrospective, consecutive, single-center series.\n\n\n\nSixteen airway VMPS treatment sessions were performed (5 patients). Endoscopic needle guidance was performed by OHNS. Sclerosants included ethanol and foamed bleomycin. The following data were tabulated for each patient: hospital length of stay (LOS), clinical response, and the presence/absence of airway swelling requiring prolonged intubation. Univariate analysis was performed. P < 0.05 was considered significant.\n\n\n\nThirty-one percent (5 of 16) of treatments required endoscopic guidance. Eighty-seven percent (7 of 8) of airway VMs treated with ethanol caused significant airway swelling compared to 0% (0 of 8) of airway VMs treated with bleomycin (P = 0.0004). The LOS was significantly greater for ethanol (5 ± 0.3 days) than for bleomycin (1 day, P = 0.001). Ninety-four percent (15 of 16) of airway VM treatments had at least a partial clinical response. There was no significant difference in clinical response between ethanol and bleomycin (P = 0.30).\n\n\n\nEndoscopic and image-guided needle placement may be necessary to treat deep airway VMs. Bleomycin may cause less significant airway swelling than ethanol. This may reduce hospital LOS and prolonged intubation. Our results should be interpreted with caution because this is a very small retrospective study. Additional investigation is needed to establish safety and efficacy of foamed bleomycin.\n\n\n\n4. Laryngoscope, 126:2726-2732, 2016.", "affiliations": "Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.", "authors": "Azene\|Ezana\|E\|;Mitchell\|Sally\|S\|;Radvany\|Martin\|M\|;Agrawal\|Nishant\|N\|;Eisele\|David\|D\|;Weiss\|Clifford\|C\|", "chemical_list": "D001761:Bleomycin", "country": "United States", "delete": false, "doi": "10.1002/lary.26077", "fulltext": null, "fulltext_license": null, "issn_linking": "0023-852X", "issue": "126(12)", "journal": "The Laryngoscope", "keywords": "Vascular anomaly; bleomycin; percutaneous sclerotherapy; venous malformation", "medline_ta": "Laryngoscope", "mesh_terms": "D000328:Adult; D000704:Analysis of Variance; D001761:Bleomycin; D002648:Child; D005260:Female; D006801:Humans; D007400:Interprofessional Relations; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010348:Patient Care Team; D012189:Retrospective Studies; D015911:Sclerotherapy; D054079:Vascular Malformations", "nlm_unique_id": "8607378", "other_id": null, "pages": "2726-2732", "pmc": null, "pmid": "27437862", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Foamed bleomycin sclerosis of airway venous malformations: The role of interspecialty collaboration.", "title_normalized": "foamed bleomycin sclerosis of airway venous malformations the role of interspecialty collaboration" }	[ { "companynumb": "US-TEVA-743117USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "65033", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MALFORMATION VENOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oral candidiasis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AZENE E, MITCHELL S, RADVANY M, AGRAWAL N, EISELE D, WEISS C. FOAMED BLEOMYCIN SCLEROSIS OF AIRWAY VENOUS MALFORMATIONS: THE ROLE OF INTERSPECIALTY COLLABORATION. 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FOAMED BLEOMYCIN SCLEROSIS OF AIRWAY VENOUS MALFORMATIONS: THE ROLE OF INTERSPECIALTY COLLABORATION. 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FOAMED BLEOMYCIN SCLEROSIS OF AIRWAY VENOUS MALFORMATIONS: THE ROLE OF INTERSPECIALTY COLLABORATION. 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{ "abstract": "Mechanical thrombectomy is a procedure used for the treatment of acute ischemic stroke in patients with large vessel occlusions. Usually with a low complication rate, we present a case with a complication post-thrombectomy not previously described in the literature noted on imaging as \"blooming artifact\".", "affiliations": "Tidelands Health Myrtle Beach South Carolina.;University of South Carolina School of Medicine Columbia South Carolina.;Scripps Mercy San Diego California.;University of South Carolina School of Medicine Columbia South Carolina.", "authors": "Coward\|John\|J\|;Prier\|Jillian\|J\|https://orcid.org/0000-0002-5943-1345;Duda\|Julian\|J\|;Yallapragada\|Anil\|A\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2753", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2753\nCCR32753\nCase Report\nCase Reports\nPost‐thrombectomy intracranial blooming artifact\nCOWARD et al.Coward John \n1\n Prier Jillian https://orcid.org/0000-0002-5943-1345\n2\n\n3\[email protected] Duda Julian \n4\n Yallapragada Anil \n2\n\n3\n \n1 \nTidelands Health\nMyrtle Beach\nSouth Carolina\n\n\n2 \nUniversity of South Carolina School of Medicine\nColumbia\nSouth Carolina\n\n\n3 \nPRISMA Health Richland\nColumbia\nSouth Carolina\n\n\n4 \nScripps Mercy\nSan Diego\nCalifornia\n\n* Correspondence\n\nJillian Prier, PRISMA Health Richland, Department of Neurology, 8 Medical Park Dr., Suite 420, Columbia, SC, 29203.\n\nEmail: [email protected]\n\n02 6 2020 \n8 2020 \n8 8 10.1002/ccr3.v8.81361 1364\n10 8 2019 05 1 2020 24 1 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nMechanical thrombectomy is a procedure used for the treatment of acute ischemic stroke in patients with large vessel occlusions. Usually with a low complication rate, we present a case with a complication post‐thrombectomy not previously described in the literature noted on imaging as “blooming artifact”.\n\nMechanical thrombectomy is a procedure used for the treatment of acute ischemic stroke in patients with large vessel occlusions. Usually with a low complication rate, we present a case with a complication post‐thrombectomy not previously described in the literature noted on imaging as “blooming artifact”.\n\n\nartifactbloomingstrokethrombectomy source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:28.08.2020\n\n\nCoward \nJ \n, \nPrier \nJ \n, \nDuda \nJ \n, \nYallapragada \nA \n. Post‐thrombectomy intracranial blooming artifact\n. Clin Case Rep . 2020 ;8 :1361 –1364\n. 10.1002/ccr3.2753\n==== Body\n1 INTRODUCTION\nMechanical thrombectomy is a recanalization procedure used standardly for the treatment of acute ischemic stroke patients with large vessel occlusions. Complications from this procedure are uncommon. Those that have been reported are symptomatic intracranial hemorrhage within 36 hours, subarachnoid hemorrhage (SAH), air emboli, vessel dissection, major groin complications, and emboli to new vascular territories.1, 2, 3\n\n\nWe present a case of a patient who received mechanical thrombectomy, and on post procedure imaging was found to have artifact suggestive of a retained stent retriever or catheter remnant.\n\n2 CASE REPORT\nThe patient is a 24‐year‐old G3P0020 at 27 weeks’ gestation who presented to an outside hospital with acute onset of right‐sided face, arm and leg weakness with expressive aphasia and a NIHSS of 14. She was treated with IV tPA and then transported to our institution for mechanical thrombectomy. Upon arrival, her NIHSS remained 14 with a clinical syndrome consistent with a left MCA distribution stroke.\n\nOn examination, the patient was in distress with a remarkable expressive aphasia. She was able to follow commands but had difficulties in both naming and repetition. She had significant right facial weakness and right arm more than right leg weakness. There was normal left‐sided function, no neglect, no visual field defects, and no ataxia on examination.\n\nThe patient was immediately taken for repeat head Computed Tomography (CT), which did not show any acute ischemic changes or hemorrhagic conversion. A Computed Tomography Angiography (CTA) of the head and neck was then performed, which showed a complete occlusion in the left M1 segment (Figure 1). The CT perfusion demonstrated a large area of penumbra and relatively small core infarct. The RAPID software on perfusion predicted a cerebral blood flow (core) of 34.2 mL and perfusion (Tmax > 6.0 seconds) volume of 77.1 mL. The mismatch volume was estimated at 42.9 mL with a mismatch ratio of 2.3 (Figure 2).\n\nFigure 1 CTA showing left M1 occlusion 1/9/17\n\nFigure 2 CT Perfusion using iSchemaView RAPID Software 1/9/17\n\nThe patient was taken for mechanical thrombectomy. Three passes were initially attempted to retrieve the thrombus using the Solitaire™ 6 × 20 stent retrieval device without success. On the fourth pass, a 3 Max catheter was then inserted in a coaxial fashion and successfully aspirated the thrombus. A 68 catheter was also utilized in this procedure; however, it was unable to advance beyond the base of the carotid siphon and, therefore, did not take part in the aspiration. Follow‐up arteriogram demonstrated Thrombolysis in Cerebral Infarction Score (TICI) 3 with complete reperfusion (Figure 3).\n\nFigure 3 Cerebral Angiogram showing TICI 3 reperfusion post‐thrombectomy 1/9/17\n\nA follow‐up MRI the following day showed mild mass effect in the left lateral ventricle without hydrocephalus or significant midline shift. A susceptibility artifact in the left insular cortex adjacent to the site of the thrombus was identified to be a “Blooming artifact” (Figure 4). By the time the MRI was performed and the artifact was discovered, the devices used during the procedure were already discarded. It was too late to look at the devices themselves and see if there was anything missing. The Blooming artifact was visualizable in sagittal, coronal, and axial views in all sequences, including but not limited to DWI, AVC, FLAIR, and GRE. A CT scan was also performed, on which the Blooming artifact was not visualizable.\n\nFigure 4 Axial, T2 tirm‐tra‐dark fluid MR Brain without contrast showing Blooming Artifact 1/10/17\n\nThe patient improved to a NIHSS of 10 after 24 hours. A hypercoagulable panel was performed and found Factor V Leiden negative, protein S normal, protein C low, PT/PTT test normal, dilute Russell viper venom test (DRVVT) negative for antiphospholipid inhibitor, and factor VIII high. A transesophageal echocardiogram showed a small patent foramen ovale (PFO). Given her small PFO and new stroke, an ultrasound of the legs was obtained. This did not show any evidence of deep venous thrombosis. The stroke was still deemed cryptogenic, with a possible etiology of cardio‐embolic given her PFO.\n\nWe obtained an additional MRI of the brain on hospital day five to better characterize the artifact. The study again showed an identical picture of the previous MRI with a circular, blooming artifact in the left MCA distribution. We felt this was a metallic artifact from the catheter device. As a result, the patient was placed on dual antiplatelet therapy (DAPT).\n\nThe patient continued to improve with inpatient rehabilitation. She gained significant improvement in language and was able to walk with only mild assistance after 1 week. She was discharged home, on DAPT, with home health physical therapy after 8 days. Her NIHSS on discharge was 3.\n\nThe patient was discharged on hospital day sixteen and instructed to follow‐up in 4‐6 weeks. Prior to outpatient follow‐up, she delivered, at 39 weeks and 1 day gestation, a healthy female infant at 1034 g with APGAR scores of 8 and 9. She showed improved symptoms on follow‐up with mild aphasia and drift for an NIHSS of 2. A follow‐up CT angiogram showed patent anterior, middle, and posterior cerebral arteries with no flow‐limiting stenoses evident. No transcranial doppler was performed. Additional MRI continued to demonstrate the artifact, and the decision was made to keep her DAPT. Six months later, DAPT was discontinued, due to bruising, in favor of single aspirin 81mg for global stroke secondary prevention.\n\n3 DISCUSSION\nCatheter remnants after mechanical thrombectomy are a complication that has not been reported in the literature for stroke. Interestingly, catheter remnants are a rare, but reported complication of coronary catheterization and angioplasty, as well as endovascular treatment of intracranial aneurysms.4, 5 On MRI, a paramagnetic material produces a susceptibility artifact known as a “Blooming” artifact due to the interference generated in the magnetic fields. This could be due to a catheter remnant, hemosiderin from a previous hemorrhage, or gas from an air embolism.6, 7, 8 We deemed nothing else possible given the nature of the procedure.\n\nThe complication rate in acute neuro‐endovascular thrombectomy procedures is uncommon and felt to be an acceptable risk given the proven benefits. In a 2016 study of 176 patients, there were complications in 20 of 176 patients (11%). A total of 23 different adverse events were reported including sICH 8 of 176 (5%), emboli to new vascular territories 4 of 176 (2%), dissection 3 of 176 (2%), vasospasm 5 of 176 (3%), stent dislocation in 1 of 42 (2%), and stent occlusion in 2 of 42 (5%).9\n\n\nIn the SWIFT trial data, 18 of 144 (12.5%) patients had complications including symptomatic intracranial hemorrhage (4.9%), air emboli (1.4%), vessel dissection (4.2%), major groin complications (2.8%), and emboli to new vascular territories (0.7%).10\n\n\nComparing the Merci with the Solitaire FR retrieval device, the main complications were symptomatic cerebral hemorrhage (10.9% vs 1.1%; P = .013); symptomatic SAH (7.3% vs 1.1%; P = .07), air emboli (1.8% vs 1.1%; P = 1.0), emboli to new vascular territories (1.8% vs 0%; P = .38), vessel dissection (1.8% vs 4.5%; P = .65), and major groin complications (3.6% vs 7.9%; P = .48). Angiographic vasospasm was common but without clinical sequelae.10\n\n\nAccording to the 2019 update of the AHA guidelines for early management of patients with acute ischemic stroke, the first attempt was made with the stent retriever based on level 1A evidence. However, for subsequent cases the choice of aspiration vs. stent retrieval device should be made based on the comfort and/or expertise of the performing proceduralist. Given the rarity of the complication, it should not alter practice in how endovascular recanalization of acute stroke is performed.11\n\n\nWe present a novel complication in this case as we suspect this “Blooming” artifact seen on MRI was in fact a catheter remnant. Unless otherwise contraindicated, MRI is frequently performed as part of the ongoing stroke work‐up to understand both the degree of injury, pathophysiology, and mechanism of the stroke. If a Blooming artifact is present, this should raise suspicion of a possible catheter remnant and subsequent antiplatelet therapy.\n\nAs we were unable to find many reported cases of this complication, we did not have good quality of evidence on how to manage this patient. The question presented was as follows: should she be placed on dual antiplatelets for a short period of time the transition into monotherapy or should she stay on DAPT lifelong?\n\nSome anecdotal evidenced‐based guidance can be inferred from the cardiac literature where catheter remnants are a reported complication in as many as 1% of cases of percutaneous coronary interventions (PCI). Endovascular retrieval of the entrapped remnants is the preferred option; however, this is not always possible and repeated failed attempts carry the risk of perioperative complications, such as vessel perforation. Conservative medical management with DAPT can be indicated if the patient remains asymptomatic, but patients experiencing ischemia due to thrombosis of the catheter remnants require emergency coronary artery bypass grafting.4 Unfortunately, unlike PCI, bypass grafting is not an available salvage option for failed medical management of intracranial catheter remnants.\n\n4 CONCLUSION\nMuch like the presence of a bare‐metal endovascular stent within the cerebral vasculature, catheter fragments can be viewed clinically as a foreign body, representing a risk for future ischemic events if not managed appropriately. It is the opinion of the authors that medical management should include DAPT with aspirin and clopidogrel, as long as the catheter fragments are present. We will continue to monitor with follow‐up imaging.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nJohn Coward: served as a member of medical team for the case and primary author of the case report. Jillian Prier: served as a secondary author and primary editor of the case report. Julian Duda: served as a senior resident of the medical team for the case. Anil Yallapragada: served as attending physician for the case.\n\nACKNOWLEDGMENTS\nSouvik Sen, MD, MS, MPH, University of South Carolina School of Medicine, PRISMA Health Richland\n==== Refs\nREFERENCES\n1 \n\nMcCarthy \nDJ \n, \nDiaz \nA \n, \nSheinberg \nDL \n, et al. Long‐term outcomes of mechanical thrombectomy for stroke: a meta‐analysis\n. Sci World J . 2019 ;2019 :1 ‐9\n.\n2 \n\nSaver \nJL \n, \nGoyal \nM \n, \nBonafe \nA \n, et al. Stent‐retriever thrombectomy after intravenous t‐PA vs. t‐PA alone in stroke\n. N Engl J Med . 2015 ;372 (24 ):2285 ‐2295\n.25882376 \n3 \n\nMeltzer \nA \n, \nSiracuse \nJJ \n, \nParrack \nI \n, \nHuang \nZ \n, \nGill \nH \n. Complications of the endovascular management of acute ischemic stroke\n. Vasc Health Risk Manag . 2014 ;10 :675 ‐681\n.25506222 \n4 \n\nVentosa‐Fernandez \nG \n, \nMoscoso \nB \n, \nCartañá \nR \n, \nPereda \nD \n. Surgical rescue after left anterior descending catheter entrapment causing cardiogenic shock\n. Interact Cardiovasc Thorac Surg . 2016 ;24 (1 ):140 ‐142\n.27624352 \n5 \n\nYasuda \nR \n, \nMaeda \nM \n, \nUmino \nM \n, et al. Suspected metallic embolism following endovascular treatment of intracranial aneurysms\n. Am J Neuroradiol . 2016 ;37 (9 ):1696 ‐1699\n.27102315 \n6 \n\nGreenberg \nSM \n, \nVernooij \nMW \n, \nCordonnier \nC \n, et al. Cerebral microbleeds: a guide to detection and interpretation\n. Lancet Neurol . 2009 ;8 (2 ):165 ‐174\n.19161908 \n7 \n\nHwang \nY \n, \nKim \nY‐J \n. Retrograde cerebral venous air embolism on susceptibility‐weighted imaging\n. Can J Neurol Sci . 2018 ;45 (4 ):464 ‐465\n.29747705 \n8 \n\nYan \nS \n, \nChen \nQ \n, \nZhang \nX \n, et al. Extensive blooming artifact predicts no recanalization after intravenous thrombolysis\n. Eur J Neurol . 2015 ;23 (4 ):737 ‐743\n.26706832 \n9 \n\nBehme \nD \n, \nGondecki \nL \n, \nFiethen \nS \n, \nKowoll \nA \n, \nMpotsaris \nA \n, \nWeber \nW \n. Complications of mechanical thrombectomy for acute ischemic stroke—a retrospective single‐center study of 176 consecutive cases\n. Neuroradiology . 2014 ;56 (6 ):467 ‐476\n.24668181 \n10 \n\nAkins \nPT \n, \nAmar \nAP \n, \nPakbaz \nRS \n, \nFields \nJD \n. Complications of endovascular treatment for acute stroke in the SWIFT trial with solitaire and Merci devices\n. Am J Neuroradiol . 2013 ;35 (3 ):524 ‐528\n.24029392 \n11 \n\nPowers \nWJ \n, \nRabinstein \nAA \n, \nAckerson \nT \n, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association\n. Stroke . 2019 ;50 (12 ):e1 ‐e75\n.\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2050-0904", "issue": "8(8)", "journal": "Clinical case reports", "keywords": "artifact; blooming; stroke; thrombectomy", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "1361-1364", "pmc": null, "pmid": "32884754", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": "25882376;29747705;27102315;24029392;19161908;26706832;27624352;25506222;31662037;24668181", "title": "Post-thrombectomy intracranial blooming artifact.", "title_normalized": "post thrombectomy intracranial blooming artifact" }	[ { "companynumb": "US-BAYER-2020-192878", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": null }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "23.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "COWARD J, PRIER J, DUDA J, YALLAPRAGADA A. POST?THROMBECTOMY INTRACRANIAL BLOOMING ARTIFACT. CLINICAL CASE REPORTS. 2020?8:8:1361?1364", "literaturereference_normalized": "post thrombectomy intracranial blooming artifact", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200921", "receivedate": "20200921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18288352, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "The most common presentations of nontuberculous mycobacterial infections in kidney transplant recipients (KTR) are cutaneous and disseminated diseases. Pleuropulmonary infection not associated with disseminated disease is rare. Its diagnosis can be difficult, requiring a combination of clinical, radiological, and bacteriological criteria. We report on a Mycobacterium avium complex pulmonary infection in a KTR with underlying chronic obstructive pulmonary disease. Chest computed tomography showed an excavated lesion of the right upper lobe, similar to a typical lesion of pulmonary tuberculosis. Evolution was favorable with multiple-drug therapy including rifampicin, ethambutol, and clarithromycin, along with a slight reduction in immunosuppression. We review the literature and discuss the epidemiology, diagnosis, management, and follow-up of this uncommon post-transplant complication.", "affiliations": "Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Medical School, Brussels, Belgium.", "authors": "Ho\|T A\|TA\|;Rommelaere\|M\|M\|;Coche\|E\|E\|;Yombi\|J-C\|JC\|;Kanaan\|N\|N\|", "chemical_list": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D007166:Immunosuppressive Agents; D017291:Clarithromycin", "country": "Denmark", "delete": false, "doi": "10.1111/j.1399-3062.2009.00473.x", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "12(2)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": null, "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D017291:Clarithromycin; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009162:Mycobacterium avium; D009894:Opportunistic Infections; D011183:Postoperative Complications; D013183:Sputum; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary", "nlm_unique_id": "100883688", "other_id": null, "pages": "138-42", "pmc": null, "pmid": "19929882", "pubdate": "2010-04", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Nontuberculous mycobacterial pulmonary infection in renal transplant recipients.", "title_normalized": "nontuberculous mycobacterial pulmonary infection in renal transplant recipients" }	[ { "companynumb": "BE-PFIZER INC-2016149718", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atypical mycobacterial lower respiratory tract infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HO, T.. NONTUBERCULOUS MYCOBACTERIAL PULMONARY INFECTION IN RENAL TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2010;12 (2):138-142", "literaturereference_normalized": "nontuberculous mycobacterial pulmonary infection in renal transplant recipients", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160422", "receivedate": "20160314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12179272, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "Management of frequent epileptic seizures in febrile infection-related epilepsy (FIRES) is often challenging. FIRES is an uncommon disease condition. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes. However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES. We present the case of a previously healthy 3-year-old male with new-onset status epilepticus (SE) admitted to the paediatric intensive care unit for 55 days. Despite treatment with multiple anti-epileptic agents in addition to IV anaesthetics, the patient remained in SRSE and continued to have generalised epileptic activity on electroencephalography (EEG). KD therapy was initiated on the 14th day of the onset, and the patient achieved complete neurological recovery following the KD. Throughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. The convulsions were well controlled after discharge. We discuss the treatment strategies for FIRES and highlight the role of KD therapy in the acute phase to control disease progression and improve the prognosis, and early diagnosis of FIRES and early initiation of KD therapy combined with anti-epileptic drugs (AEDs) could improve the prognosis.", "affiliations": "Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.", "authors": "Li\|Wen-Jing\|WJ\|;Xue\|Chun-Ling\|CL\|;Zhang\|Yong\|Y\|;Wu\|Li-Hui\|LH\|;Chen\|Dong-Mei\|DM\|;Chen\|Feng\|F\|;Xu\|Jing\|J\|;Li\|Zhuo\|Z\|;Miao\|Hong-Jun\|HJ\|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/tp-21-121", "fulltext": "\n==== Front\nTransl Pediatr\nTransl Pediatr\nTP\nTranslational Pediatrics\n2224-4336\n2224-4344\nAME Publishing Company\n\n34733679\ntp-10-09-2392\n10.21037/tp-21-121\nCase Report\nKetogenic diet (KD) therapy in the acute phase of febrile infection-related epilepsy syndrome (FIRES): a case report\nLi Wen-Jing 1 ^\nXue Chun-Ling 2\nZhang Yong 1\nWu Li-Hui 2\nChen Dong-Mei 2\nChen Feng 1\nXu Jing 1\nLi Zhuo 2\nMiao Hong-Jun 2\n1 Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China;\n2 Department of Emergency, Children’s Hospital of Nanjing Medical University, Nanjing, China\nCorrespondence to: Zhuo Li; Hong-Jun Miao. Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China. Email: [email protected]; [email protected].\n^ ORCID: 0000-0003-1684-4390.\n\n9 2021\n9 2021\n10 9 23922397\n25 3 2021\n29 6 2021\n2021 Translational Pediatrics. All rights reserved.\n2021\nTranslational Pediatrics.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nManagement of frequent epileptic seizures in febrile infection-related epilepsy (FIRES) is often challenging. FIRES is an uncommon disease condition. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes. However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES. We present the case of a previously healthy 3-year-old male with new-onset status epilepticus (SE) admitted to the paediatric intensive care unit for 55 days. Despite treatment with multiple anti-epileptic agents in addition to IV anaesthetics, the patient remained in SRSE and continued to have generalised epileptic activity on electroencephalography (EEG). KD therapy was initiated on the 14th day of the onset, and the patient achieved complete neurological recovery following the KD. Throughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. The convulsions were well controlled after discharge. We discuss the treatment strategies for FIRES and highlight the role of KD therapy in the acute phase to control disease progression and improve the prognosis, and early diagnosis of FIRES and early initiation of KD therapy combined with anti-epileptic drugs (AEDs) could improve the prognosis.\n\nKeywords:\n\nFebrile infection-related epilepsy syndrome (FIRES)\nstatus epilepticus (SE)\nketogenic diet (KD)\nacute phase\ncase report\n==== Body\npmcIntroduction\n\nFebrile infection-related epilepsy syndrome (FIRES) describes an acute-onset, potentially fatal epileptic encephalopathy that develops in previously healthy children and adolescents during or soon after afebrile episode or any other infectious disease. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes (1). The annual incidence of FIRES among children and adolescents is 1:1,000,000 and 1:100,000, respectively (2). FIRES mainly affects children aged 3–15 years old (3), with a peak during school age and male predominance (4).\n\nThe proposed consensus definition of 2018 identifies FIRES as a subcategory of new-onset refractory status epilepticus (NORSE) (5), with a history of febrile infection, a history of fever between 2 weeks and 24 h prior to the onset of refractory status epilepticus (SE), and the seizure during the epileptic episode is often refractory to drugs. The pathogenesis underlying FIRES is still a matter of debate, and the clinical outcome of FIRES is poor (2).\n\nThe most important treatment for FIRES is the control of epileptic seizures, especially during the acute phase (6). Although general expert consensus in the literature recommends the administration of anti-epileptic drugs (AEDs) or anticonvulsants, they are ineffective in most cases of FIRES (7). However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES.\n\nHerein, we report the case of a 3-year-old boy with FIRES, in whom we focused on KD therapy in the acute phase and ultimately achieved complete neurological recovery after extensive treatment.\n\nCase presentation\n\nClinical data\n\nA 3-year-old boy with normal development and no other symptoms of metabolic disease had an onset of intermittent fever for 11 days, which quickly progressed to seizures.\n\nHis vital signs included a temperature of 38.5 °C, blood pressure of 112/72 mmHg, a pulse of 153 beats per minute, and a respiratory rate of 20 breaths per minute. A venous blood gas analysis showed a sodium level of 129 mmol/L, potassium 4.3 mmol/L, and pH 7.33. The results of the investigations revealed a white blood cell (WBC) count of 14.12×109/L (reference range 4×109–10×109/L), chest X-ray films revealed dense flocculent shadow in both the lungs, electroencephalography (EEG) revealed a generalised background slowing and frequent right-sided electrical activity, magnetic resonance imaging (MRI) showed clear atrophy, and a lumbar puncture followed by an analysis of the cerebrospinal fluid showed normal results. Based on these, the diagnosis was central nervous system infection, viral encephalitis, SE, and bronchopneumonia.\n\nTreatment\n\nAnti-infectives, anti-epileptics, and relevant symptomatic treatment were administered.\n\nAnti-infective therapy\n\nGiven the risk of the possibility of co-infection with bacteria, viruses, and mycoplasma, the patient was immediately initiated on anti-infective therapy.\n\nThe patient was treated empirically with cefodizime following admission to our pediatric intensive care unit, considering his body temperature of 38.5 °C and WBC count of 14.12×109/L. However, he continued to have a recurrent fever with a higher thermal peak than before, and cefodizime was changed to meropenem. Due to the drug-drug interactions between meropenem and anti-epileptic agents affecting seizure control, ceftazidime was resumed again when the infection was better controlled following three consecutive routine blood examinations. Ceftazidime was discontinued once the results of the routine blood tests showed a return to normal values, and no abnormalities were found on chest radiography after 2 weeks of treatment. However, his fever recurred 3 days later with a febrile peak of 38.5 °C. The results of routine blood examination showed C-reactive protein (CRP) of 18 mg/L, WBC count of 19.65×109/L, and 0.991 ng/mL of procalcitonin (PCT), and the sputum culture identified Burkholderia cepacia. Based on the results of the drug susceptibility test, it was decided to administer meropenem. After a 5-day treatment, meropenem was changed to ceftazidime when the results of the blood culture were negative for Burkholderia cepacia but showed sensitivity to ceftazidime. Anti-infective treatment was intensified by the addition of sulfamethoxazole tablets because the tracheal intubation culture was positive for Burkholderia cepacia and Staphylococcus aureus, and the CRP level and WBC counts were higher than before. After treatment with ceftazidime and compound sulfamethoxazole tablets for 3 weeks, the patient was discharged when his health was in better condition.\n\nDrug selection and dose adjustment were tailored according to the clinical manifestations, indicators of infection, and results of the culture. The anti-infective treatment regimen is listed in (Table 1), and the indicators of infections and body temperature during the anti-infective therapy are shown in (Figure 1).\n\nTable 1 Anti-infective treatment regimen of the patient during hospitalization\n\nDate\tDrugs\tDosage\tEtiological examination\tComments\t\n9.15–9.17\tCefodizime\t0.6 g, bid, ivgtt\t–\tExperiential therapy\t\n9.18–9.24\tMeropenem\t0.3 g, q8h, ivgtt\t–\tInfection aggravated\t\n9.25–10.4\tCeftazidime\t0.75 g, q12h, ivgtt\t–\tEffective control of infection\t\n10.5–10.8\tAzithromycin\t0.125 g, qd, po\tHaemophilus influenza (+)\tSputum culture\t\n10.11–10.15\tMeropenem\t0.25 g, q8h, ivgtt\tBurkholderia cepacia (+)\tSputum culture\t\n10.16–10.27\tCeftazidime\t0.625 g, q12h, ivgtt\tBurkholderia cepacia (+)\tSputum culture\t\n10.28–11.14\tCeftazidime\t0.625 g, q12h, ivgtt\tBurkholderia cepacia (+)\tTracheal intubation culture\t\nSulfamethoxazole\t0.24 g, q12h, po\tStaphylococcus aureus (+)\tInfection aggravated\t\n\nFigure 1 The infectious indicators and body temperature of the patient during hospitalization. CRP, C-reactive protein; WBC, white blood cell; PCT, procalcitonin.\n\nThe patient was treated with acyclovir and voriconazole for 3 weeks because he tested positive for Epstein-Barr (EB) virus and a fungus, and erythromycin for 2 weeks because he tested positive for Mycoplasma pneumoniae IgG.\n\nAnti-epileptic therapy\n\nDespite broad-spectrum AED therapies (topiramate, levetiracetam, phenytoin sodium, and clonazepam), the patient had frequent epileptic seizures, especially tonic-clonic seizures. A midazolam infusion was initiated and up-titrated to 0.3 mg kg−1 h−1; however, it failed to achieve burst suppression, and the patient continued to have generalised epileptic activity on EEG.\n\nWhile these agents were being titrated, KD therapy was initiated on the 14th day of the onset, and screening for hematuria and B-scan examination of the hepatobiliary tree, pancreas, and spleen were performed before initiating KD therapy.\n\nThe classic KD calculates the ratio of grams of fat to grams of carbohydrates plus protein. The most feasible ratios calculated to date are 3:1 or 4:1, with approximately 80%–90% of the energy provided by fats and 10% by carbohydrates and proteins collectively (8). The patient received enteral KD (EN KD) consisting of a commercially available ketogenic formula (KD milk powder) and a commercially available fat emulsion with medium-chain triglycerides (Peptamen Junior). His body temperature was stable, and the seizure frequency, seizure type, and intervals between the seizures were significantly improved after approximately 1-month of KD therapy. The formula for KD therapy and the corresponding outcome are listed in (Table 2).\n\nTable 2 The formula of KD therapy and the improving symptom of seizure\n\nDate\tSeizure frequency\tSeizure\ntypes\tGrand mal\tRelief time of seizure\tFormula of KD (q3h)\t\nKD milk powder (g)\tPeptamen Junior (g)\tWater (mL)\t\n9.15–9.27\tContinuous\ta\t√\t1–5 min\t–\t–\t–\t\n9.28\tContinuous\ta\t√\t1–5 min\t6.8\t0.5\t50\t\n9.29\tContinuous\ta\t√\t1–5 min\t13.5\t1.0\t70\t\n9.30–10.4\tContinuous\tb\t–\t1–3 min\t13.5\t1.0\t70\t\n10.5–10.7\tContinuous\tb\t–\t1–3 min\t14.0\t0.4\t70\t\n10.8–10.11\tParoxysmal\tc\t–\t1–2 min\t14.0\t0.4\t70\t\n10.12–10.17\tParoxysmal\tc\t–\t1–2 min\t15.5\t–\t80\t\n10.18–10.20\tParoxysmal\tc\t–\t1–2 min\t16.5\t–\t80\t\n10.21–10.22\tParoxysmal\td\t–\t30 s\t16.5\t–\t80\t\n10.23–10.27\tOccasional\td\t–\t30 s\t16.0\t2.3\t80\t\n10.28\tOccasional\td\t–\t30 s\t11.0\t11.0\t90\t\n10.29–10.30\tOccasional\td\t–\t15 s\t–\t22.0\t90\t\n10.31–11.5\tOccasional\te\t–\t15 s\t–\t–\t–\t\n11.6–11.14\t–\t–\t–\t–\t–\t–\t–\t\na, visible generalised convulsions, elevated muscle tone, and dribbling at the mouth; b, rhythmic muscle twitches, elevated muscle tone, and tonic eye deviation; c, rhythmic muscle twitches, twitching in the face and nystagmoid, or rhythmic eye movements; d, Elevated muscle tone, gazed in both eyes and skewed angles of the mouth; e, rhythmic muscle twitches and dribbling at the mouth. KD, ketogenic diet.\n\nDuring the KD therapy, electrolytes, arterial blood gases, serum ketone bodies, and glucose were monitored, and these indicators were checked again once the blood ketone level was above 5.5 mmol/L or the blood glucose level was below 2.5 mmol/L. There were no symptoms of hypoglycaemia or hyper ketoacidosis with blood ketone level of 1.2–4.9 mmol/L and blood glucose 2.7–7.9 mmol/L.\n\nRelevant symptomatic treatment\n\nThe patient was administered mannitol and glycerol fructose alternately to reduce the intracranial pressure, and the dosage and frequency were gradually reduced according to the clinical status during the treatment. The combination of dextro-ibuprofen suppository with physical cooling was effective in reducing the body temperature with recurrent fever during the course of the disease.\n\nPrognosis\n\nThroughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. He was continued on topiramate, levetiracetam, phenytoin sodium, and clonazepam and was ultimately discharged on the AED regimen.\n\nThe patient continued rehabilitation after discharge from the hospital. Follow-up visits were made 1 to 2 months after discharge and the convulsions were well controlled; however, the patient was lost to follow-up 6 months after discharge.\n\nDiscussion\n\nWe present a case of a rare epilepsy syndrome with unclear aetiology in a healthy boy who ultimately recovered completely after extensive treatment, especially KD therapy, during the acute phase. The clinical outcome warrants discussion as FIRES is typically considered a life-threatening condition with mortality up to 30% and intellectual disability in 66–100% of the survivors (9,10).\n\nSince there are no known causes, and no disease markers or genetic testing are available for the diagnosis, FIRES is typically diagnosed at a late stage in the clinical course (4), which is primarily based on the clinical status in children with preceding fever who develop refractory SE after known causes of SE have been excluded (9).\n\nIn this particular case of FIRES, none of the anti-epileptic therapeutic approaches appeared to be significantly effective, with the exception of KD.\n\nKD contains high fat content, low carbohydrate content, and adequate protein content. It alters the primary cerebral energy supply from glucose to ketone bodies, mimicking biochemical changes during starvation (11,12). KD is the most effective when taken after fasting or when the body’s calorie levels are low. This is because the brain normally uses glucose as a source of energy rather than fats. However, glucose levels are low in the fasting state; thus, the brain utilises fats as the source of energy in such circumstances (13). Although the exact mechanisms underlying the anticonvulsive activity of KD are still unclear, it is thought that KD has anti-epileptic activity, anti-inflammatory effects, and neuroprotective activity (14-17), making it a non-pharmacological substitute for the treatment of epilepsy. Several recent studies have indicated that KD is not only suitable for acute phase therapy but also long-term disease management (18,19). In addition to traditional AEDs, early KD treatment was helpful for both seizure control and cognitive outcome after FIRES (20,21).\n\nConclusions\n\nIn summary, this challenging case of FIRES in a previously healthy boy emphasises the importance of early initiation of KD in the acute phase. Despite the high risk of mortality and the difficulty in controlling frequent epileptic seizures, clinical outcome resulted in complete neurological recovery. This case also showed that KD was an effective therapeutic option for FIRES, and early diagnosis of FIRES and early initiation of KD therapy combined with AEDs could improve the prognosis.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tp-21-121 10.21037/tp-21-121 10.21037/tp-21-121\n\nAcknowledgments\n\nFunding: None.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at https://dx.doi.org/10.21037/tp-21-121\n\nPeer Review File: Available at https://dx.doi.org/10.21037/tp-21-121\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tp-21-121). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Kramer U Chi CS Lin KL Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia 2011;52 :1956-65. 10.1111/j.1528-1167.2011.03250.x 21883180\n2 van Baalen A Häusler M Plecko-Startinig B Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012;43 :209-16. 10.1055/s-0032-1323848 22911482\n3 van Baalen A Vezzani A Häusler M Febrile Infection-Related Epilepsy Syndrome: Clinical Review and Hypotheses of Epileptogenesis. Neuropediatrics 2017;48 :5-18.27919115\n4 Gaspard N Hirsch LJ Sculier C New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia 2018;59 :745-52. 10.1111/epi.14022 29476535\n5 Hirsch LJ Gaspard N van Baalen A Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 2018;59 :739-44. 10.1111/epi.14016 29399791\n6 Serino D Santarone ME Caputo D Febrile infection-related epilepsy syndrome (FIRES): prevalence, impact and management strategies. Neuropsychiatr Dis Treat 2019;15 :1897-903. 10.2147/NDT.S177803 31371963\n7 Sculier C Gaspard N . New onset refractory status epilepticus (NORSE). Seizure 2019;68 :72-8. 10.1016/j.seizure.2018.09.018 30482654\n8 Starnes K Miller K Wong-Kisiel L A Review of Neurostimulation for Epilepsy in Pediatrics. Brain Sci 2019;9 :283. 10.3390/brainsci9100283 31635298\n9 Caraballo RH Reyes G Avaria MF Febrile infection-related epilepsy syndrome: a study of 12 patients. Seizure 2013;22 :553-9. 10.1016/j.seizure.2013.04.005 23643626\n10 Appenzeller S Helbig I Stephani U Febrile infection-related epilepsy syndrome (FIRES) is not caused by SCN1A, POLG, PCDH19 mutations or rare copy number variations. Dev Med Child Neurol 2012;54 :1144-8. 10.1111/j.1469-8749.2012.04435.x 23066759\n11 Klepper J. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 2008;49 Suppl 8 :46-9. 10.1111/j.1528-1167.2008.01833.x 19049586\n12 Yang H Wu J Guo R Glycolysis in energy metabolism during seizures. Neural Regen Res 2013;8 :1316-26.25206426\n13 Anwar H Khan QU Nadeem N Epileptic seizures. Discoveries (Craiova) 2020;8 :e110. 10.15190/d.2020.7 32577498\n14 Liu F Peng J Zhu C Efficacy of the ketogenic diet in Chinese children with Dravet syndrome: A focus on neuropsychological development. Epilepsy Behav 2019;92 :98-102. 10.1016/j.yebeh.2018.12.016 30641252\n15 Nabbout R Mazzuca M Hubert P Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51 :2033-7. 10.1111/j.1528-1167.2010.02703.x 20813015\n16 Chang P Augustin K Boddum K Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain 2016;139 :431-43. 10.1093/brain/awv325 26608744\n17 Dupuis N Curatolo N Benoist JF Ketogenic diet exhibits anti-inflammatory properties. Epilepsia 2015;56 :e95-8. 10.1111/epi.13038 26011473\n18 Singh RK Joshi SM Potter DM Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet. Pediatrics 2014;134 :e1431-5. 10.1542/peds.2013-3106 25332495\n19 Nangia S Caraballo RH Kang HC Is the ketogenic diet effective in specific epilepsy syndromes? Epilepsy Res 2012;100 :252-7. 10.1016/j.eplepsyres.2012.01.015 22424762\n20 Fox K Wells ME Tennison M Febrile Infection-Related Epilepsy Syndrome (FIRES): A Literature Review and Case Study. Neurodiagn J 2017;57 :224-33. 10.1080/21646821.2017.1355181 28898171\n21 Appavu B Vanatta L Condie J Ketogenic diet treatment for pediatric super-refractory status epilepticus. Seizure 2016;41 :62-5. 10.1016/j.seizure.2016.07.006 27475280\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2224-4336", "issue": "10(9)", "journal": "Translational pediatrics", "keywords": "Febrile infection-related epilepsy syndrome (FIRES); acute phase; case report; ketogenic diet (KD); status epilepticus (SE)", "medline_ta": "Transl Pediatr", "mesh_terms": null, "nlm_unique_id": "101649179", "other_id": null, "pages": "2392-2397", "pmc": null, "pmid": "34733679", "pubdate": "2021-09", "publication_types": "D002363:Case Reports", "references": "27919115;31371963;20813015;26011473;29476535;22911482;29399791;27475280;22424762;28898171;19049586;26608744;25206426;30641252;21883180;23066759;31635298;30482654;25332495;23643626;32577498", "title": "Ketogenic diet (KD) therapy in the acute phase of febrile infection-related epilepsy syndrome (FIRES): a case report.", "title_normalized": "ketogenic diet kd therapy in the acute phase of febrile infection related epilepsy syndrome fires a case report" }	[ { "companynumb": "CN-UCBSA-2022005695", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Seizure", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KEPPRA" }, { "actiondrug": null, "activesubstance": { 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Ketogenic diet (KD) therapy in the acute phase of febrile infection-related epilepsy syndrome (FIRES): A case report. Translational Pediatrics. 2021;10(9):2392-7", "literaturereference_normalized": "ketogenic diet kd therapy in the acute phase of febrile infection related epilepsy syndrome fires a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220210", "receivedate": "20220210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20456353, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]
{ "abstract": "OBJECTIVE\nTo determine the efficacy and safety of intra-cardiac lidocaine administration to induce fetal demise before second-trimester medication abortion in a teaching hospital in Addis Ababa, Ethiopia.\n\n\nMETHODS\nWe performed a retrospective chart review to collect selected sociodemographic and clinical information. All patients who received fetal intra-cardiac lidocaine between January 1, 2019 and April 30, 2019 were included in the study. Fetal demise was considered successful if achieved within 24 hours after fetal intra-cardiac lidocaine administration. We analyzed the data using SPSS version 20. We used frequency tables to describe the data and performed a multivariable analysis to determine associations between variables.\n\n\nRESULTS\nA total of 80 fetuses were given intra-cardiac lidocaine.The mean gestational age was 23+1 weeks (range 21+0 -27+5 weeks). Twenty-four hours after lidocaine administration 76 (95%) pregnancies showed negative fetal cardiac activity. Fetuses at gestational ages of 21-23+6 weeks were five times more likely to have negative cardiac activity compared with those with gestational ages between 24 and 28 weeks (P=0.001). Two women developed nausea, vomiting, and a metallic taste, but no serious adverse events were reported.\n\n\nCONCLUSIONS\nIntra-cardiac lidocaine is effective at inducing fetal demise before late second-trimester medication abortion with no associated serious adverse events or complications.", "affiliations": "Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, University of Michigan, Ann Arbor, MI, USA.;Department of Obstetrics, Gynecology and Reproductive Science, University of Vermont, Burlington, VT, USA.;Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, University of Michigan, Ann Arbor, MI, USA.", "authors": "Tolu\|Lemi Belay\|LB\|;Tufa\|Tesfaye H\|TH\|;Abas\|Ferid\|F\|;Kahn\|Chavi\|C\|;MacAfee\|Lauren\|L\|;Prager\|Sarah\|S\|;Bell\|Jason D\|JD\|", "chemical_list": "D008012:Lidocaine", "country": "United States", "delete": false, "doi": "10.1002/ijgo.13419", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-7292", "issue": "153(1)", "journal": "International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics", "keywords": "Ethiopia; Fetal demise; Intra-cardiac lidocaine; Late abortion; Lidocaine; Medication abortion", "medline_ta": "Int J Gynaecol Obstet", "mesh_terms": "D000028:Abortion, Induced; D000293:Adolescent; D000328:Adult; D005002:Ethiopia; D005260:Female; D005313:Fetal Death; D005318:Fetal Heart; D005865:Gestational Age; D006801:Humans; D008012:Lidocaine; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "0210174", "other_id": null, "pages": "125-129", "pmc": null, "pmid": "33043458", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Intra-cardiac lidocaine administration to induce fetal demise before late second-trimester abortion: Retrospective review.", "title_normalized": "intra cardiac lidocaine administration to induce fetal demise before late second trimester abortion retrospective review" }	[ { "companynumb": "ET-ALKEM LABORATORIES LIMITED-ET-ALKEM-2021-02171", "fulfillexpeditecriteria": "1", "occurcountry": "ET", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "4", "drugadministrationroute": "016", "drugauthorizationnumb": "207810", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal death", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "207810", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Abortion induced", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Tolu LB, Tufa TH, Abas F, Kahn C, et al.. Intra-cardiac lidocaine administration to induce fetal demise before late second-trimester abortion: Retrospective review. 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Intra-cardiac lidocaine administration to induce fetal demise before late second-trimester abortion: Retrospective review. 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{ "abstract": "The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored.\n\n\n\nPatients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ).\n\n\n\nBetween 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3).\n\n\n\nGastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.", "affiliations": "Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgery, Nieuwegein, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Biometrics, Amsterdam, the Netherlands.;Department of Gastrointestinal Oncology, Amsterdam, the Netherlands.;Department of Medical Oncology, St Antonius Hospital, Nieuwegein, the Netherlands.;Department of Pharmacy, Amsterdam, the Netherlands.;>Department of Clinical Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgery, Nieuwegein, the Netherlands.;Department of Surgery, Nieuwegein, the Netherlands.;Department of Gastrointestinal Oncology, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.", "authors": "van der Kaaij\|R T\|RT\|;Wassenaar\|E C E\|ECE\|;Koemans\|W J\|WJ\|0000-0003-0101-081X;Sikorska\|K\|K\|;Grootscholten\|C\|C\|;Los\|M\|M\|;Huitema\|A\|A\|;Schellens\|J H M\|JHM\|;Veenhof\|A A F A\|AAFA\|;Hartemink\|K J\|KJ\|;Aalbers\|A G J\|AGJ\|;van Ramshorst\|B\|B\|;Boerma\|D\|D\|;Boot\|H\|H\|;van Sandick\|J W\|JW\|", "chemical_list": "D000970:Antineoplastic Agents; D000077150:Oxaliplatin; D000077143:Docetaxel", "country": "England", "delete": false, "doi": "10.1002/bjs.11588", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1323", "issue": "107(11)", "journal": "The British journal of surgery", "keywords": null, "medline_ta": "Br J Surg", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D005743:Gastrectomy; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms; D013274:Stomach Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "0372553", "other_id": null, "pages": "1520-1528", "pmc": null, "pmid": "32277764", "pubdate": "2020-10", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Treatment of PERItoneal disease in Stomach Cancer with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy: PERISCOPE I initial results.", "title_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results" }	[ { "companynumb": "NL-SA-2020SA123570", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021492", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "460 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "460", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterocutaneous fistula", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DER KAAIJ R.T.? WASSENAAR E.C.E.? KOEMANS W.J.? SIKORSKA K., GROOTSCHOLTEN C., LOS M. ET AL. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. BR J SURG. 2020?UNKNOWN:UNKNOWN", "literaturereference_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200515", "receivedate": "20200515", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17792177, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "NL-SA-2020SA123538", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021492", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "460 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "460", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Aspiration", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Postoperative ileus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DER KAAIJ R.T.? WASSENAAR E.C.E.? KOEMANS W.J., SIKORSKA K., GROOTSCHOLTEN C., LOS M. ET AL. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. BR J SURG. 2020?UNK:UNK", "literaturereference_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20200515", "receivedate": "20200515", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17792166, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "NL-PFIZER INC-2019170928", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "033", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "460 MG/M2, (HYPERTHERMIC OXALIPLATIN (30 MINUTES),FIXED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "460", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "033", "drugauthorizationnumb": "022234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, (NORMOTHERMIC DOCETAXEL (90 MINUTES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aspiration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Ileus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DER KAAIJ, R.. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. BRITISH JOURNAL OF SURGERY. 2020?107 (11):1520-1528", "literaturereference_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20201229", "receivedate": "20190422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16225155, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" }, { "companynumb": "NL-PFIZER INC-2019171151", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "033", "drugauthorizationnumb": "022234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, (NORMOTHERMIC DOCETAXEL (90 MINUTES))", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "033", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "460 MG/M2, (HYPERTHERMIC OXALIPLATIN (30 MINUTES),FIXED DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "460", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Postoperative ileus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DER KAAIJ, R.. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. BRITISH JOURNAL OF SURGERY. 2020?107 (11):1520-1528", "literaturereference_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20201228", "receivedate": "20190422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16224983, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" } ]
{ "abstract": "Pure red cell aplasia (PRCA) is characterised by an anaemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with the selective absence of erythroid precursor cells. Drug-induced PRCA is a rare cause of secondary erythroid aplasia, but distinct from the primary and most secondary forms, it is usually acute and fully reversible upon withdrawal of the causative drug. We report a 36 year-old Chinese man who developed diphenylhydantoin associated PRCA two months after commencing the treatment. Reappearance of reticulocytes was observed six days following the cessation of diphenylhydantoin therapy and the haemoglobin level rose to normal one month later. The extreme rarity of this adverse reaction to a drug used so widely strongly suggests an individual predisposition.", "affiliations": "Department of Medicine, National University of Singapore.", "authors": "Kueh\|Y K\|YK\|;Yeo\|T C\|TC\|;Choo\|M H\|MH\|", "chemical_list": "D010672:Phenytoin", "country": "Singapore", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0304-4602", "issue": "20(3)", "journal": "Annals of the Academy of Medicine, Singapore", "keywords": null, "medline_ta": "Ann Acad Med Singap", "mesh_terms": "D000328:Adult; D006801:Humans; D008297:Male; D010672:Phenytoin; D012010:Red-Cell Aplasia, Pure", "nlm_unique_id": "7503289", "other_id": null, "pages": "407-9", "pmc": null, "pmid": "1929190", "pubdate": "1991-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Reversible pure red cell aplasia associated with diphenylhydantoin therapy.", "title_normalized": "reversible pure red cell aplasia associated with diphenylhydantoin therapy" }	[ { "companynumb": "SG-PFIZER INC-2018381925", "fulfillexpeditecriteria": "1", "occurcountry": "SG", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL HAEMATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1990", "drugstartdateformat": "602", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "THROMBOSIS PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "198904", "drugstartdateformat": "610", "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KUEH, Y.. REVERSIBLE PURE RED CELL APLASIA ASSOCIATED WITH DIPHENYLHYDANTOIN THERAPY. ANNALS OF THE ACADEMY OF MEDICINE. 1991?20(3):407?409", "literaturereference_normalized": "reversible pure red cell aplasia associated with diphenylhydantoin therapy", "qualification": "1", "reportercountry": "SG" }, "primarysourcecountry": "SG", "receiptdate": "20180928", "receivedate": "20180925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15425241, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "BACKGROUND\nThe aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage.\n\n\nMETHODS\nSixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded.\n\n\nRESULTS\nBaseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08).\n\n\nCONCLUSIONS\nAt the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.", "affiliations": "Department of Cardiac Surgery, University of Munich, Grosshadern Medical Center, Marchioninistrasse 15, 81366 Munich, Germany. [email protected]", "authors": "Meiser\|Bruno M\|BM\|;Groetzner\|Jan\|J\|;Kaczmarek\|Ingo\|I\|;Landwehr\|Peter\|P\|;Müller\|Markus\|M\|;Jung\|Sebastian\|S\|;Uberfuhr\|Peter\|P\|;Fraunberger\|Peter\|P\|;Stempfle\|Hans-Ulrich\|HU\|;Weis\|Michael\|M\|;Reichart\|Bruno\|B\|", "chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1097/01.tp.0000129814.52456.25", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1337", "issue": "78(4)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases; D016572:Cyclosporine; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D006949:Hyperlipidemias; D007166:Immunosuppressive Agents; D007668:Kidney; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D016559:Tacrolimus; D017211:Treatment Failure", "nlm_unique_id": "0132144", "other_id": null, "pages": "591-8", "pmc": null, "pmid": "15446320", "pubdate": "2004-08-27", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?", "title_normalized": "tacrolimus or cyclosporine which is the better partner for mycophenolate mofetil in heart transplant recipients" }	[ { "companynumb": "DE-CONCORDIA PHARMACEUTICALS INC.-E2B_00010164", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 X 125 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "0.03 TO 0.1 MG/KG/DAY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "AS A SHORT-TERM INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021959", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aspergillus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MEISER B,GROETZNER J,KACZMAREK I,LANDWEHR P,MULLER M,JUNG S. TACROLIMUS OR CYCLOSPORINE: WHICH IS THE BETTER PARTNER FOR MYCOPHENOLATE MOFETIL IN HEART TRANSPLANT RECIPIENTS?.. TRANSPLANTATION 2004 AUG 27?78 (4)::591-598.", "literaturereference_normalized": "tacrolimus or cyclosporine which is the better partner for mycophenolate mofetil in heart transplant recipients", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180228", "receivedate": "20180228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14579934, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]
{ "abstract": "This study sought to report pregnancy outcomes in women following cardiac transplantation.\n\n\n\nThis was a descriptive retrospective cohort study of women with pregnancies following cardiac transplantation managed at two large tertiary centres in Canada and Belgium between 2001 and 2017.\n\n\n\nSixteen women had 17 singleton pregnancies following cardiac transplantation. The mean maternal age was 28 ± 5.8, and the transplant-to-pregnancy interval was 7.3 ± 4.0 years. There were two first trimester terminations, one for teratogenicity concerns and the other because of a maternal cardiac condition. There was one spontaneous miscarriage. All women had normal left ventricular function at the start of pregnancy. Graft rejection occurred in two women. Other maternal complications included anemia requiring blood transfusion (n = 5), renal failure or deterioration (n = 4), preeclampsia (n = 2), and urine infections (n = 2). The mean GA at delivery was 35 ± 3.5 weeks. Six infants were born preterm, and two were small-for-gestational-age. Fetal anomalies were identified in two pregnancies. Women were followed after pregnancy for a median of 5.6 years (range, 10 months to 15 years). Although there were no deaths during pregnancy, two women died at 10 and 18 months after delivery.\n\n\n\nWith appropriate multidisciplinary care, women with cardiac transplants can have successful pregnancies. Although rates of fetal loss are low, these women continue to be at risk for graft rejection, preterm birth, other pregnancy-related complications, and cardiovascular death.", "affiliations": "Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON. Electronic address: rohan.d'[email protected].;Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.;Division of Cardiology, Pregnancy and Heart Disease Program, Department of Medicine, Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON.;Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON.;Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.;Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.;Division of Cardiology, Pregnancy and Heart Disease Program, Department of Medicine, Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON.;Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON.;Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, ON.", "authors": "D'Souza\|Rohan\|R\|;Soete\|Elisabeth\|E\|;Silversides\|Candice K\|CK\|;Zaffar\|Nusrat\|N\|;Van Mieghem\|Tim\|T\|;Van Cleemput\|Johan\|J\|;Bhagra\|Catriona\|C\|;Sermer\|Mathew\|M\|;Ross\|Heather\|H\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jogc.2017.08.030", "fulltext": null, "fulltext_license": null, "issn_linking": "1701-2163", "issue": "40(5)", "journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC", "keywords": "Cardiac transplantation; management; outcomes; pregnancy; pregnancy complications", "medline_ta": "J Obstet Gynaecol Can", "mesh_terms": "D000328:Adult; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "101126664", "other_id": null, "pages": "566-571", "pmc": null, "pmid": "29153738", "pubdate": "2018-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Pregnancy Outcomes Following Cardiac Transplantation.", "title_normalized": "pregnancy outcomes following cardiac transplantation" }	[ { "companynumb": "CA-ASTELLAS-2018US026021", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adactyly", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "D^SOUZA R, SOETE E, SILVERSIDES CK, ZAFFAR N, VAN MIEGHEM T, VAN CLEEMPUT J ET AL. PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. J OBSTET GYNAECOL CAN. 2018?40(5):566-71", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20180608", "receivedate": "20180608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14987814, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "CA-BRISTOL-MYERS SQUIBB COMPANY-BMS-2018-055735", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "9 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "D^SOUZA R, SOETE E, SILVERSIDES KC, ZAFFAR N, VAN MIEGHEM T, VAN CLEEMPUT J, ET AL. PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA. 2018?40(5):566?71", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20210212", "receivedate": "20180627", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15073029, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "CA-ASTELLAS-2018US026022", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysplasia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "D^SOUZA R, SOETE E, SILVERSIDES CK, ZAFFAR N, VAN MIEGHEM T, VAN CLEEMPUT J ET AL. PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA. 2018?40(5):566-71", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20180608", "receivedate": "20180608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14987450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-04399", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "9 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COUMADIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "D^SOUZA R, SOETE E, SILVERSIDES CK, ZAFFAR N, ET AL. PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA. 2018?40(5):566-571", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190101", "receivedate": "20190101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15779521, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]
{ "abstract": "BACKGROUND\nReports have demonstrated the superior activity of combining both irinotecan and oxaliplatin (FOLFOXIRI) therapy. An option for gaining similar benefits with less toxicity would be the administration of irinotecan through a hepatic artery approach. The aim of this study was to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis.\n\n\nMETHODS\nPatients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival.\n\n\nRESULTS\nThe intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs 31%) and extrahepatic disease (56% vs 32%, P = .02). The median numbers of chemotherapy cycles were similar (10 vs 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm at 2 (78% vs 54%, P = .02), 4 (95% vs 70%, P = .03), and 6 months (76% vs 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs 16%, P = .05), and there was improved median progression-free survival (15.3 vs 7.6 months).\n\n\nCONCLUSIONS\nThe simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This strategy leads to improved overall response rates, improved hepatic progression-free survival, and more durable overall progression-free survival in patients downsized to resection.", "affiliations": "Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, Kentucky.;Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, Kentucky.;Clearview Cancer Institute, Huntsville, Alabama.;Froedtert Medical College, Milwaukee, Wisconsin.;Interventional Radiology, Sutter Health, Sacramento, California.;Norton Radiology Associates, Louisville, Kentucky.;Norton Radiology Associates, Louisville, Kentucky.;Hospital Italiano, Buenos Aires, Argentina.;James Graham Brown Cancer Center, Louisville, Kentucky.;Providence Medical Center, Portland, Oregon.;Siteman Cancer Center, Washington University in Saint Louis/Barnes-Jewish Hospital, Saint Louis, Missouri.", "authors": "Martin\|Robert C G\|RC\|;Scoggins\|Charles R\|CR\|;Schreeder\|Marshall\|M\|;Rilling\|William S\|WS\|;Laing\|Christopher J\|CJ\|;Tatum\|Clifton M\|CM\|;Kelly\|Lawrence R\|LR\|;Garcia-Monaco\|Ricardo D\|RD\|;Sharma\|Vivek R\|VR\|;Crocenzi\|Todd S\|TS\|;Strasberg\|Steven M\|SM\|", "chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin", "country": "United States", "delete": false, "doi": "10.1002/cncr.29534", "fulltext": null, "fulltext_license": null, "issn_linking": "0008-543X", "issue": "121(20)", "journal": "Cancer", "keywords": "hepatic artery therapy; irinotecan; liver-directed therapy; liver-dominant metastatic colorectal cancer; metastatic colon cancer", "medline_ta": "Cancer", "mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D015179:Colorectal Neoplasms; D016503:Drug Delivery Systems; D005472:Fluorouracil; D006499:Hepatic Artery; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D016896:Treatment Outcome", "nlm_unique_id": "0374236", "other_id": null, "pages": "3649-58", "pmc": null, "pmid": "26149602", "pubdate": "2015-10-15", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis.", "title_normalized": "randomized controlled trial of irinotecan drug eluting beads with simultaneous folfox and bevacizumab for patients with unresectable colorectal liver limited metastasis" }	[ { "companynumb": "US-CIPLA LTD.-2015US08601", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "077219", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "50 MG/ML FOR A TOTAL DOSE OF 100 MG PER VIAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "5", "activesubstance": { 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RANDOMIZED CONTROLLED TRIAL OF IRINOTECAN DRUG-ELUTING BEADS WITH SIMULTANEOUS FOLFOX AND BEVACIZUMAB FOR PATIENTS WITH UNRESECTABLE COLORECTAL LIVER-LIMITED METASTASIS. CANCER. 2015?3649-3658", "literaturereference_normalized": "randomized controlled trial of irinotecan drug eluting beads with simultaneous folfox and bevacizumab for patients with unresectable colorectal liver limited metastasis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151120", "receivedate": "20151120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11756911, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "BACKGROUND\nOmalizumab is a non-steroidal medication indicated for the treatment of poorly controlled moderate-to-severe allergic asthmatics. This observational study examines the \"real world\" effectiveness of omalizumab in this population.\n\n\nMETHODS\nThis is a one year open-label observational study that compared clinical outcomes including total oral corticosteroid use, exacerbation history, measures of quality of life and inflammation in patients with moderate-to-severe allergic asthma, who were prescribed omalizumab as part of their treatment with the year prior to therapy.\n\n\nRESULTS\nA total of 99 patients were enrolled at 25 sites in Canada. During the study period, the mean total annual OCS dose was reduced from 2301.5 mg (prednisone equivalents) in the year prior to omalizumab to 1130.0 mg (p<0.0001). There was a 71% reduction in asthma exacerbations and 56% of patients on omalizumab remained exacerbation free when compared to the year prior to study entry. Associated with this was reduced health care utilization. There were significant improvements in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) Patients with an elevated FeNO at baseline showed a better response to treatment. No new safety issues were identified during the study period.\n\n\nCONCLUSIONS\nOur study demonstrates that in \"real world\" clinical practice, after initiating omalizumab, there is a reduction in total OCS use and exacerbation frequency in patients with moderate-to-severe allergic asthma. Patients on treatment reported improved asthma control and quality of life. FeNO may be a useful biomarker to identify patients who may benefit with omalizumab treatment.", "affiliations": "Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;Ottawa Allergy Research Corporation, University of Ottawa, Ottawa, Ontario, Canada.;Clinique Spécialisée en Allergie de la Capitale, Quebec City, Quebec, Canada.;Novartis Pharmaceuticals Canada Inc., Montreal, Quebec, Canada.;Novartis Pharmaceuticals Canada Inc., Montreal, Quebec, Canada.", "authors": "Bhutani\|Mohit\|M\|http://orcid.org/0000-0002-7535-6613;Yang\|William H\|WH\|;Hébert\|Jacques\|J\|;de Takacsy\|Frederica\|F\|;Stril\|Jean-Louis\|JL\|", "chemical_list": "D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D005938:Glucocorticoids; D000069444:Omalizumab; D009569:Nitric Oxide; D011241:Prednisone", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0183869", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0183869PONE-D-17-12144Research ArticleMedicine and Health SciencesPulmonologyAsthmaMedicine and Health SciencesHealth CareQuality of LifeResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsResearch and Analysis MethodsResearch DesignObservational StudiesMedicine and Health SciencesPulmonologyRespiratory InfectionsResearch and Analysis MethodsResearch DesignSurvey ResearchQuestionnairesMedicine and Health SciencesHealth CareHealth Care PolicyTreatment GuidelinesMedicine and Health SciencesCritical Care and Emergency MedicineThe real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma: The ASTERIX Observational study The ASTERIX Observational studyhttp://orcid.org/0000-0002-7535-6613Bhutani Mohit ConceptualizationInvestigationMethodologyWriting – original draftWriting – review & editing1Yang William H. ConceptualizationInvestigationMethodologyWriting – original draftWriting – review & editing2Hébert Jacques ConceptualizationInvestigationMethodologyWriting – original draftWriting – review & editing3de Takacsy Frederica ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationResourcesWriting – original draftWriting – review & editing4Stril Jean-Louis ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesValidationWriting – original draftWriting – review & editing41 \nDepartment of Medicine, University of Alberta, Edmonton, Alberta, Canada2 \nOttawa Allergy Research Corporation, University of Ottawa, Ottawa, Ontario, Canada3 \nClinique Spécialisée en Allergie de la Capitale, Quebec City, Quebec, Canada4 \nNovartis Pharmaceuticals Canada Inc., Montreal, Quebec, CanadaFehrenbach Heinz EditorForschungszentrum Borstel Leibniz-Zentrum fur Medizin und Biowissenschaften, GERMANYCompeting Interests: MB, WHY and JH received honoraria as part of the steering committee for the development of the research protocol. MB, WHY and JH are or have been members of Novartis Advisory Boards. J-LS and FdT are employees of Novartis Pharmaceuticals Canada Inc. J-LS is Therapeutic Area Head, Respiratory Division and FdT is the Group Head, Local Clinical Research Operations. This commercial affiliation of J-LS and FdT does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.\n\n E-mail: [email protected] 8 2017 2017 12 8 e018386928 3 2017 11 8 2017 © 2017 Bhutani et al2017Bhutani et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nOmalizumab is a non-steroidal medication indicated for the treatment of poorly controlled moderate-to-severe allergic asthmatics. This observational study examines the “real world” effectiveness of omalizumab in this population.\n\nMethods\nThis is a one year open-label observational study that compared clinical outcomes including total oral corticosteroid use, exacerbation history, measures of quality of life and inflammation in patients with moderate-to-severe allergic asthma, who were prescribed omalizumab as part of their treatment with the year prior to therapy.\n\nResults\nA total of 99 patients were enrolled at 25 sites in Canada. During the study period, the mean total annual OCS dose was reduced from 2301.5 mg (prednisone equivalents) in the year prior to omalizumab to 1130.0 mg (p<0.0001). There was a 71% reduction in asthma exacerbations and 56% of patients on omalizumab remained exacerbation free when compared to the year prior to study entry. Associated with this was reduced health care utilization. There were significant improvements in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) Patients with an elevated FeNO at baseline showed a better response to treatment. No new safety issues were identified during the study period.\n\nConclusion\nOur study demonstrates that in “real world” clinical practice, after initiating omalizumab, there is a reduction in total OCS use and exacerbation frequency in patients with moderate-to-severe allergic asthma. Patients on treatment reported improved asthma control and quality of life. FeNO may be a useful biomarker to identify patients who may benefit with omalizumab treatment.\n\nhttp://dx.doi.org/10.13039/100009009Novartis Pharmaceuticals CanadaMB, WHY and JH received honoraria as part of the steering committee for the development of the research protocol. MB, WHY and JH are members of Novartis Advisory Boards. Novartis Pharmaceuticals Canada Inc. provided funding for the development and implementation of this observational study. This included support for the individual sites to collect data for the duration of the study. They also funded the analysis of the study. No study medication was funded by Novartis as this was an observational trial only. Study medication was supplied through public and private payers, as the patients enrolled in the study met the Canadian product monograph for the utilization of omalizumab in the severe asthma population. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nAsthma is a chronic inflammatory airway disease characterized by variable airflow obstruction. Asthmatics are able to achieve control of their symptoms by limiting environmental exposures that may aggravate their asthma and by using medications such as inhaled corticosteroids (ICS) to reduce the inflammation associated with the disease.\n\nHowever, there remains a population of asthmatics who, despite guideline-based treatment, continue to have poor control and experience acute exacerbations [1]. These patients often require oral corticosteroids (OCS) to control their disease. OCS are associated with a number of side effects including osteoporosis, cataracts and the potential for Cushing’s syndrome [2]. Since asthma is more severe in older adults [3], reducing the burden of OCS is of high importance.\n\nApproximately 90% of asthma is allergic in nature [4]. Omalizumab is a biologic humanized IgE neutralizing antibody (anti-IgE) that binds to circulating IgE, prevents binding to the receptor thereby inhibiting the allergic-inflammatory cascade [5]. Omalizumab provides a non-steroidal treatment option for asthmatics with moderate to severe persistent allergic asthma, whose symptoms are inadequately controlled with high dose ICS [6]. Previously, omalizumab has been shown to reduce the number of asthma exacerbations, improve symptom severity, and improve the quality of life in such patients [7–9]. It is currently recommended in many asthma guidelines, including the Canadian guidelines [1], as part of a treatment algorithm [10].\n\nThe purpose of this study is to understand the ‘real world’ efficacy and safety of omalizumab in the treatment of patients with moderate-to-severe allergic asthma (the ASTERIX Observational study). The primary aim of this study was to evaluate the corticosteroid-sparing effect of omalizumab in these patients.\n\nMethods\nStudy design\nThis was a pan Canadian, multicenter, 12-month, open-label single-arm study. At each institution, the research protocol was reviewed by the institutions ethics board (see below) and the study received institutional approval. This study is an observational study of patient related outcomes. The study medication is already approved for use in Canada, and the patients enrolled in the study were deemed to be appropriate for the use of omalizumab, as per the indications on the Canadian product monograph. Our study is assessing a real life response to the therapy. The study began in August 2012 (first patient, first visit) and completed in October 2014 (last patient, last visit). The study collected retrospective and prospective information from subjects who were to be prescribed omalizumab in routine clinical practice as per the Canadian Product Monograph [6]. Eligible study participants had inadequately-controlled asthma, defined as either: 1) having experienced two or more severe asthma exacerbations requiring treatment with OCS in the 12 months preceding study enrolment despite treatment with high dose ICS plus at least one other controller agent; or 2) requiring a maintenance dose of OCS for at least 3 months prior to study enrolment, independent of exacerbation history. During the study, subjects received treatment for their asthma and any acute asthma exacerbations as clinically indicated and as per usual medical practice.\n\nStudy eligibility criteria excluded subjects previously treated with omalizumab, subjects with a respiratory tract infection in the month prior to study start, current smokers or subjects with a smoking history of >10 pack-years, subjects with severe co-morbidities, or subjects who were pregnant or lactating.\n\nBaseline assessments were completed prior to the first omalizumab injection and subjects were then assessed every three months during the study. At each assessment, pulmonary function was measured, medication use and exacerbation data were collected. The term “severe asthma exacerbation” was defined for this study as one that required treatment with systemic (oral or IV) corticosteroids and/or that resulted in a hospitalization or emergency department visit. Subjects also completed the Asthma Control Questionnaire (ACQ) and the Asthma Quality of Life Questionnaire (AQLQ). The ACQ is a seven-item questionnaire that is a validated assessment of asthma symptom control [11,12]. The AQLQ is a disease-specific, self-administered quality of life questionnaire [13] which can be used to evaluate the impact of asthma treatment over the prior 14 days.\n\nFractional exhaled nitric oxide (FeNO) was measured in a subset of enrolled subjects at 10 sites. Each of the 10 sites participating in this exploratory analysis had access to appropriate equipment for measuring FeNO, using standardized techniques and calibration procedures. Two FeNO tests were conducted on each subject at every study visit, and the reported value was the mean of 2 values that were within 10% of each other.\n\nRetrospective data for a period of 12 months prior to the first omalizumab injection was collected from subject charts for comparison with data collected from the 12-month prospective study period. This data included: cumulative systemic corticosteroid dosage, frequency and severity of asthma exacerbations, symptom scores, quality-of-life data and health care utilization [14].\n\nEfficacy outcomes\nThe primary endpoint was the mean change in total annual OCS dose during the prospective treatment period as compared to the year prior to the start of omalizumab treatment. Secondary endpoints included the number (%) of subjects who reduced/stopped OCS use, the number (%) of subjects experiencing severe asthma exacerbations, the mean number of severe asthma exacerbations per subject, mean duration of severe asthma exacerbations, changes in ACQ, AQLQ and FeNO while receiving omalizumab as compared to baseline or the prior year. Health resource utilization data was also collected prospectively and compared to the prior year.\n\nSafety outcomes\nOnly serious adverse events were collected for study purposes.\n\nStatistical analysis/outcome measures\nStatistical analyses were performed using the intent-to-treat (ITT) population. Descriptive statistics for continuous variables are presented with number of subjects, mean, standard deviation, median, minimum, and maximum. Comparisons between the prospective treatment period and retrospective data were performed using paired t-tests. Categorical variables were summarized with number and percentage of subjects. All hypotheses were based on two-sided tests using a 5% level of significance. The 95% confidence interval was calculated for the absolute difference between the treatment groups. Any other statistical tests were assessed at the 2-sided, 5% significance level.\n\nThe study protocol was approved by the institutional ethics board for each site, and all subjects (or parents/guardians when appropriate) provided written informed consent prior to any study-related evaluations. The following are the names of the ethics board/committee for each site involved in the study: Institutional Review Board Services (IRB Services), Aurora, Ontario; The Health Research Ethics Board (HREB)—Biomedical Panel, University of Alberta; Research Ethics Review Committee (RERC), Edmonton, Alberta; McGill University Health Center–Research Ethic Board (MUHC-REB), University of McGill; Comité d’Éthique à la Recherche–Centre Hospitalier de l’Université de Montréal (CER-CHUM), Centre Hospitalier de l’Université de Montréal; Comité d’Éthique à la Recherche–Institut Universitaire de Cardiologie et Pneumologie de Québec (CER IUCPQ), Institut Universitaire de Cardiologie et Pneumologie de Québec; University of British Columbia–Clinical Research Ethic Board (UBC CREB), University of British Columbia; University of British Columbia–Providence Health Care–Research Ethics Board (UBC-PHC REB, University of British Columbia.\n\nResults\nA total of 99 subjects were enrolled at 25 sites in Canada. All subjects received at least one dose of omalizumab during the study period. Twenty-one subjects (21.2%) discontinued the study. The primary reasons for discontinuation were loss to follow-up (9 subjects), administrative reasons (5 subjects), adverse events (4 subjects) and subject no longer required study drug (3 subjects). Of the 4 subjects who discontinued due to adverse events, there were 3 serious and one non-serious event: 1 case of pregnancy, 1 case of anaphylactic reaction, 1 case of severe asthma and one subject who discontinued due to an unspecified non-serious adverse event.\n\nTable 1 summarizes baseline characteristics. The subjects were predominantly female, white and with a mean age of 48. On average, they experienced 2.4 exacerbations in the year prior to starting treatment. Baseline medications are in keeping with current standards of asthma management.\n\n10.1371/journal.pone.0183869.t001Table 1 Demographics and baseline characteristics.\nBaseline characteristics n = 99\t\nAge (years)\tMean (SD)\t47.8 (13.8)\t\nRange\t12–77\t\nGender, n (%)\tMale\t31 (31.3%)\t\n\tFemale\t68 (68.7%)\t\nRace, n (%)\tWhite\t87 (87.9%)\t\nBlack\t5 (5.1%)\t\nAsian\t5 (5.1%)\t\nNative American\t2 (2.0%)\t\nWeight (kg)\tMean (SD)\t79.6 (19.7)\t\nRange\t37–139\t\nDuration of asthma (years)\tMean (SD)\t20.9 (15.4)\t\nSmoking history, n (%)\tNever smoked\t63 (63.6%)\t\nEx-smoker\t36 (36.4%)\t\nFEV1 (L)\tMean (SD)\t2.2 (0.8)\t\nFEV1 (% predicted)\tMean (SD)\t72.9 (20.1)\t\nIgE levels (ng/mL)\tMean (SD)\t668.1 (937.0)\t\n\nExacerbations in 12 months before baseline visit\tMean (SE)\t2.4 (0.14)\t\nMean (SE)\t2.4 (0.14)\t\nRange\t0.0–8.0\t\nAsthma Medications taken at Visit 1\tInhaled Corticosteroids\t46 (46.5%)\t\nLong-Acting Bronchodilators\t3 (3.0%)\t\nLABA/ICS (combination)\t93 (93.9%)\t\nLeukotriene Receptor Antagonists\t52 (52.5%)\t\nLABA = Long Acting Bronchodilator; ICS = Inhaled Corticosteroid.\n\nA subject could have had more than one type of asthma medication.\n\nAll but one subject had documented prior systemic corticosteroid use. The majority used OCS periodically for the treatment of asthma exacerbations and 25% used a daily OCS maintenance dose for asthma management. When treated with omalizumab, the mean total annual OCS dose (expressed in prednisone equivalents) was reduced from 2301.5 mg (SE 374.3 mg) to 1130.0 mg (SE 307.5 mg) (p<0.0001) (Table 2). 70.8% of subjects either stopped or were able to reduce the dose of OCS by 40% or more.\n\n10.1371/journal.pone.0183869.t002Table 2 Mean change in total annual oral corticosteroid (OCS) dose [1] (ITT population).\n\tRetrospective Period\tProspective Period\t\nN\t96\t96\t\nMean (SE)\t2301.5 (374.3)\t1130.0 (307.5)\t\nRange\t(0.0, 30780)\t(0.0, 21840)\t\nRetrospective—Prospective [2]\t\t\n • Difference (SE)\t1171.5 (197.8)\t\n • 95% CI\t[778.8, 1564.2]\t\n • p-value\t<0.0001\t\n[1] Oral Corticosteroid values are converted to prednisone equivalents (expressed in mg).\n\n[2] Paired t-test was used to assess period differences.\n\nSE = standard error\n\nOf the 96 subjects in the ITT population with available data, 54 patients (56.3%) remained exacerbation-free during the prospective period, as compared to only 4 patients (4.2%) in the retrospective period (Table 3). The overall exacerbation frequency was reduced by 70.8% during the study period, with a mean of 0.8 severe exacerbations/patient compared to 2.4/patient in the year prior (p<0.0001). Additionally, the mean duration of severe asthma exacerbations was decreased from 39.1 to 10.9 days, (p<0.0001).\n\n10.1371/journal.pone.0183869.t003Table 3 Number (%) of subjects experiencing severe asthma exacerbations [1] and change from baseline health resource utilization (ITT population).\n\t\tRetrospective period\tProspective period\t\nSevere asthma\n Exacerbation\n\tN\t96\t96\t\nNo\t4 (4.2%)\t54 (56.3%)\t\nYes\t92 (95.8%)\t42 (43.8%)\t\nNumber of emergency department (ED) visits\tN\t95\t96\t\nMean (SE)\t1.2 (0.1)\t0.2 (0.1)\t\nMedian\t1.0\t0.0\t\nRange\t(0.0, 7.0)\t(0.0, 5.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t1.1 (0.2)\t\n• 95% CI\t[-0.8,1.4]\t\n• p-value\t<0.0001\t\nNumber of hospitalizations\tN\t96\t96\t\nMean (SE)\t0.4 (0.1)\t0.1 (0.1)\t\nMedian\t0.0\t0.0\t\nRange\t(0.0, 5.0)\t(0.0, 4.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t0.3 (0.1)\t\n• 95% CI\t[-0.1, 0.5]\t\n• p-value\t0.0081\t\nNumber of unscheduled health professional visits\tN\t87\t95\t\nMean (SE)\t3.1 (0.4)\t0.8 (0.2)\t\nMedian\t3.0\t0.0\t\nRange\t(0.0, 20.0)\t(0.0, 8.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t2.4 (0.4)\t\n• 95% CI\t[1.7, 3.1]\t\n• p-value\t<0.0001\t\nNumber of days in hospital (ED+ICU+Other)\tN\t96\t96\t\nMean (SE)\t1.8 (0.3)\t0.6 (0.3)\t\nMedian\t0.0\t0.0\t\nRange\t(0.0, 18.0)\t(0.0, 22.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t1.3 (0.4)\t\n• 95% CI\t[0.5, 2.0]\t\n• p-value\t0.0010\t\n[1] A severe asthma exacerbation had to fulfil at least one of the following criteria: 1) requiring treatment with systemic (oral or IV) corticosteroids OR 2) resulting in hospitalization or requiring an emergency department visit. Courses of corticosteroids separated by 1 week or more were treated as separate severe exacerbation events\n\n[2] Paired t-test was used to assess period differences.\n\nOmalizumab treatment resulted in improved asthma control, as shown through significant improvements in the mean ACQ total score, from 2.7 at baseline to 1.9 at month 4 (p<0.0001). This improvement was maintained until the end of the study (Table 4). In parallel, the AQLQ score improved from an average of 3.9 at baseline to 4.8 at month 4 (p<0.0001) (Table 5) and remained stable for the remainder of the study. The domain scores all improved by a similar magnitude.\n\n10.1371/journal.pone.0183869.t004Table 4 Change from baseline in Asthma Control Questionnaire (ACQ) total score [1] during the prospective period (ITT population).\n\tBaseline\tMonth 4\tMonth 8\tMonth 12\t\nN\t96\t92\t76\t86\t\nMean (SE)\t2.7 (0.1)\t1.9 (0.1)\t1.8 (0.1)\t1.9 (0.1)\t\nMedian\t2.6\t1.8\t1.7\t1.8\t\nRange\t(0.0, 5.6)\t(0.0, 4.6)\t(0.0, 4.0)\t(0.0, 4.7)\t\nBaseline—Treatment\t\t\t\t\t\n • Difference (SE)\t\t0.7 (0.1)\t1.0 (0.1)\t0.8 (0.1)\t\n • 95%CI\t\t[0.5, 1.0]\t[0.8, 1.2]\t[0.5, 1.1]\t\n • p-value\t\t<0.0001\t<0.0001\t<0.0001\t\n[1] Each question is equally weighted and the ACQ score is the mean of the 7 questions with an average value between 0 (totally controlled) and 6 (severely uncontrolled). Paired t-test was used to assess differences between baseline and treatment values.\n\n10.1371/journal.pone.0183869.t005Table 5 Change from baseline in Asthma Quality of Life Questionnaire (AQLQ) total scores during treatment with omalizumab (ITT population).\n\tBaseline\tMonth 4\tMonth 8\tMonth 12\t\nAverage Overall Score\t\nN\t96\t92\t76\t86\t\nMean (SE)\t3.9 (0.1)\t4.8 (0.1)\t5.0 (0.1)\t4.8 (0.2)\t\nMedian\t3.9\t4.9\t5.1\t4.9\t\nRange\t(1.4, 6.7)\t(1.8, 6.8)\t(1.8, 6.9)\t(1.6, 6.9)\t\nBaseline—treatment [1]\t\t\t\t\t\n • Difference (SE)\t\t-0.9 (0.1)\t-1.2 (0.1)\t-1.0 (0.2)\t\n • 95% CI\t\t[-1.2, -0.6]\t[-1.5, -0.9]\t[-1.3, -0.7]\t\n • p-value\t\t<0.0001\t<0.0001\t<0.0001\t\n[1] Paired t-test was used to assess differences between baseline and treatment values.\n\nFeNO was measured on 48 subjects during the study period. Table 6 summarizes the change in FeNO measurements over the course of the study period. Mean FeNO at baseline was 47.3 ppb (SE 5.7) and was significantly reduced by 12 months to 37.1 ppb (SE 4.6, p = 0.0258). Subjects were further divided into high (≥19.5 ppb) and low (<19.5) baseline FeNO groups for analysis purposes (Table 7) [15]. There was a higher percent reduction in total annual OCS dose and annual number of severe asthma exacerbations in the high FeNO subgroup than in the Low FeNO group. In the high FeNO group, the annual OCS dose decreased by 75% and exacerbations were reduced by 82%.\n\n10.1371/journal.pone.0183869.t006Table 6 Change from baseline in Forced Exhaled Nitric Oxide (FeNO) mean values [1] during the prospective period (ITT / FeNO population).\n\tBaseline\tMonth 4\tMonth 8\tMonth 12\t\nN\t48\t46\t47\t49\t\nMean (SE)\t47.3 (5.7)\t39.1 (5.0)\t38.0 (6.0)\t37.1 (4.6)\t\nMedian\t39.3\t26.5\t23.5\t22.0\t\nRange\t(6.5, 173.5)\t(5.5, 161.5)\t(5.0, 238.5)\t(5.0, 140.0)\t\nBaseline—treatment [2][3]\t\t\t\t\t\n • Difference(SE)\t\t7.6 (4.0)\t9.0 (4.8)\t9.9 (4.3)\t\n • 95% CI\t\t[-0.5, 15.7]\t[-0.6, 18.6]\t[1.2, 18.5]\t\n • p-value\t\t0.0660\t0.0642\t0.0258\t\n[1] The FeNO values (in ppb) used for the summary were the mean of 2 values obtained at each visit.\n\n[2] Paired t-test was used to assess differences between baseline and treatment values.\n\n[3] This analysis was conducted on a subset of subjects at 10 pre-defined sites.\n\nNote: Last observation forward methods (LOCF) were used for missing data.\n\n10.1371/journal.pone.0183869.t007Table 7 Percent change in total annual OCS dose and number of severe asthma exacerbations in Low/High FeNO baseline subgroups from baseline to end of prospective period (ITT population).\n\t\t% change in total annual OCS dose [1]\t% change in total annual number of severe asthma exacerbations [2]\t\nHigh FeNO [3]\tN\t35\t35\t\nMean (SE)\t-75.21 (5.5)\t-81.8 (4.9)\t\nMedian\t-100.0\t-100.0\t\nRange\t(-100.0, 0.3)\t(-100.0, 0.0)\t\nLow FeNO [3]\tN\t13\t13\t\nMean (SE)\t-27.6 (25.0)\t-47.4 (18.4)\t\nMedian\t-52.6\t-66.7\t\nRange\t(-100.0, 182.2)\t(-100.0, 100.0)\t\n[1] Oral corticosteroid values were converted to prednisone equivalents (mg).\n\n[2] Percent change was defined as 100(Prospective—Retrospective)/Retrospective.\n\n[3] Low FeNO = FeNO measurement <19.5 ppb at baseline; High FeNO = FeNO measurement ≥19.5 ppb.\n\nNote: Two subjects had no severe asthma exacerbation during the Retrospective period but had one during the Prospective period. Therefore, % change could not be computed for these subjects.\n\nTable 3 summarizes the change in healthcare resource utilization during the study period. The mean number of Emergency Department visits (0.2 ± 0.1 vs 1.2 ± 0.1, p<0.0001), hospitalizations (0.1 ± 0.1 vs 0.4 ± 0.1, p = 0.0081) and unscheduled healthcare professional visits (0.8 ± 0.2 vs 3.1 ± 0.4, p<0.0001) were all significantly reduced during the treatment follow up period. In addition, hospitalized subjects had a significantly reduced length of stay (0.6 ± 0.3 vs 1.8 ± 0.3 days; p<0.0010).\n\nSafety\nIn the study database, nine subjects experienced at least one SAE (Serious Adverse Event) but only one subject experienced an SAE considered by the investigator to be related to study drug. That subject had three events—dizziness of moderate intensity on the first day of treatment and 2 anaphylactic reactions of severe intensity. Omalizumab was permanently discontinued for this subject. The subject was reported to have completely recovered from these events. Table 8 summarizes all SAEs reported during the study. No safety concerns were raised from these SAEs. One subject became pregnant and was discontinued from the study.\n\n10.1371/journal.pone.0183869.t008Table 8 All Serious adverse events.\nSystem Organ Class\tOmalizumab (N = 99)\t\n Preferred Term\tn (%)\t\nInfections and Infestations\t\t\n Abscess\t1 (1%)\t\n Device related infection\t1 (1%)\t\n Post procedural infection\t1 (1%)\t\n Staphylococcal infection\t1 (1%)\t\nInjury, poisoning and procedural complications\t\n Anaemia postoperative\t1 (1%)\t\n Procedural haemorrhage\t1 (1%)\t\n Wrist fracture\t1 (1%)\t\nCardiac disorders\t\t\n Cardiac arrest\t1 (1%)\t\nGastrointestinal disorders\t\t\n Large intestinal obstruction\t1 (1%)\t\nImmune system disorders\t\t\n Anaphylactic reaction\t1 (1%)\t\nNervous system disorders\t\t\n Dizziness\t1 (1%)\t\nPregnancy, puerperium and perinatal conditions\t\n Pregnancy\t1 (1%)\t\nRenal and urinary disorders\t\t\n Renal impairment\t1 (1%)\t\nRespiratory, thoracic and mediastinal disorders\t\n Asthma\t1 (1%)\t\nDiscussion\nAmong the asthmatic population, the prevalence of severe uncontrolled asthma is approximately 10% [16,17]. These patients have a reduced quality of life and poor lung function. For many of them, systemic corticosteroids are routinely used to manage the disease, and as a result, they are prone to a variety of short and long-term adverse effects [2], which may further add to the clinical burden of this disease. In randomized clinical trials omalizumab, through its non-steroidal mechanism of action of binding free IgE molecules and preventing activation of the inflammatory cascade, has been shown to reduce asthma exacerbations and thereby reduce the need for oral corticosteroids [8,9]. However, until now the Canadian real-life effect has not been assessed. The present study was designed to evaluate the “real life” clinical benefit of omalizumab as add-on treatment for patients with poorly controlled moderate-to-severe allergic asthma, as per Canadian guidelines [1].\n\nOur results demonstrate that patients treated with omalizumab reduced their total oral corticosteroid dosing during the treatment period, when compared with the year prior. Furthermore, 50% of the patients were able to discontinue use of daily OCS during the study. There are significant benefits to this, as long-term OCS use is associated with many side effects negatively affecting a patient’s overall health. These include increased risk of infections, hypertension, cataracts, impact on bone mineral density and the potential to lead to diabetes or affect diabetic control [2].\n\nPrevention of asthma exacerbations is an important outcome of asthma treatment [1, 10]. Our study demonstrated a significant reduction in the frequency, severity and duration of asthma exacerbations. Although mortality due to asthma has decreased significantly, the morbidity and costs associated with asthma exacerbations remain elevated [16,18,19]. In our study, we saw a 71% reduction in total asthma exacerbations along with reduced health care utilization. In several studies, the improved outcomes we observed has resulted in a cost benefit favoring use of omalizumab, especially in those with severe exacerbations requiring hospitalizations [20,21].\n\nFeNO is considered to be a non-invasive marker for airway inflammation [22] and has been utilized as a surrogate marker for the presence of eosinophilic airway dysfunction. In this study, we observed a significant reduction in FeNO levels over the 1-year study period. The FeNO decrease occurred despite reduced OCS exposure, supporting the anti-inflammatory effect of omalizumab. Furthermore, the clinical benefits of omalizumab were more pronounced in patients who had high FeNO levels at baseline. There was a 75% reduction in annual OCS use and an 82% reduction in exacerbation rates in patients with a FeNO ≥19.5 ppb. This supports the findings of Hanania et al.[15] who demonstrated a similar finding in the EXTRA study. FeNO, if used as part of the clinical assessment, may further assist in identifying an omalizumab responder, which is of benefit for patient and physician.\n\nAccording to the Canadian asthma management continuum [1], improved quality of life (QoL) and symptom control are important goals of treatment. The subjects enrolled in this study had poor QoL and suboptimal control of their asthma at baseline, as measured by the ACQ and AQLQ. The AQLQ is a disease-specific questionnaire which measures the impact of asthma on symptoms, activity limitation, emotional function and environmental stimuli [13]. In this study, omalizumab treatment led to a significant improvement in AQLQ scores. The improvements were seen early, by month 4, and were maintained throughout the assessment period. In parallel, the ACQ demonstrated a similar early significant improvement in asthma symptoms and these were also maintained over the course of the study. It is important to highlight that all the improved outcomes observed during the study occurred in the setting of reduced OCS exposure, which has its own clinical merit and further supports the efficacy of omalizumab.\n\nAlthough only 5–10% of asthmatics have severe disease, they account for more than 50% of asthma-related total health costs [18,23]. Our results show that adding omalizumab to the therapeutic regimen of these severe asthmatics significantly reduced overall health care utilization. Reductions in healthcare utilization with omalizumab have been previously reported [7,9,24–26], and it is encouraging, that in “real life” application, this continues to be seen.\n\nASTERIX is an observational, open-label study and the results are consistent with published randomized clinical trials and other “real life effectiveness” studies [7–9,27], however this is the first report in a Canadian population and the first to report on the use of FeNO in “real life” Canadian clinical practice. Recently both a systematic review and meta-analysis assessing “real life effectiveness” studies of omalizumab have been published [28, 29]. The outcomes assessed and reported in those studies were similar to ours, and show that in different populations, there is a “real life effectiveness” of omalizumab in improving the outcomes for patients with severe asthma.\n\nThe results of our study in a Canadian population adds to the current literature in several capacities. First, there are inherent differences in the Canadian population than the ones studied in the systematic review and meta-analysis, as those studies were primarily European. Second, because health care systems vary between countries, the medical treatment a patient receives prior to the initiation of omalizumab may vary, and thereby affect the outcomes of previous reports. Third, demonstrating efficacy in the Canadian severe asthma population will be helpful to payers of the health care system in Canada, both private and public, who may request evidence of efficacy in order to fund this medication. Lastly, unique to our study was the measurement of FeNO in a sub-set of the study population. The impressive response to omalizumab in patient’s with high FeNO (>19.5 ppb) has not been reported in other “real life” studies. Based on both the EXTRA and Asterix study, clinicians may want to consider measuring FeNO to provide more confidence in the decision to add on omalizumab to current therapy in the uncontrolled severe asthma patient.\n\nThere are several limitations to this study. First, it is an open-label study and there is no control group for comparison. Instead, treatment effectiveness was assessed in comparison to the previous year or to patient status at baseline (AQLQ, ACQ). Second, it could be considered a weakness that some of the study data (exacerbations, OCS use and acute care visits) was collected retrospectively. However, subjects with this severity of asthma tend to be followed closely by their physicians so that there is a good record of treatment in the patient chart. If anything, some retrospective events might not have been reported and the results may therefore underestimate the treatment effect.\n\nConclusion\nIn a “real world” observational study, patients with moderate-to-severe allergic asthma who are poorly controlled despite optimized therapy with high dose ICS and another controller medication, benefit from treatment with omalizumab by reducing oral steroid use, experiencing reduced exacerbation frequency and showing improved quality of life and asthma control.\n\nGuarantor: J-LS takes responsibility (is the guarantor) of the content of the manuscript, including data and analysis.\n\nAuthor contributions: MB, WHY, JH, FdT and J-LS contributed substantially to the study design, analysis and interpretation, and the writing of the manuscript. We also acknowledge Suzanne Kelly PhD in assisting in reviewing this manuscript.\n\nRole of the sponsor: Novartis Pharmaceuticals, Canada Inc. was the sponsor of this study. Support for protocol development, study implementation, data management and statistical analysis was provided by Allphase Clinical Research Inc. and funded by Novartis Pharmaceuticals, Canada Inc.\n\nOther Contributions: We thank the physicians who participated in the ASTERIX study: Dr. Mohit Bhutani, Dr.Jacques Hebert, Dr.William H. Yang, Dr. Celine Bergeron, Dr. Stephen Betschel, Dr. Joseph Braidy, Dr. Amarjit Cheema, Dr. David Copeland, Dr. François Corbeil, Dr. Delbert Dorscheid, Dr. Tam Le Duc, Dr. J. Mark FitzGerald, Dr. Charles Frankish, Dr. Michel Laviolette, Dr. Jason K. 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Allergy \n66 : 671 –678 . doi: 10.1111/j.1398-9995.2010.02522.x \n21255035 \n25 Brusselle G , Michils A , Louis R , Dupont L , Van de Maele B , Delobbe A , et al (2009 ) \"Real-life\" effectiveness of omalizumab in patients with severe persistent allergic asthma: The PERSIST study . Respir Med \n103 : 1633 –1642 . doi: 10.1016/j.rmed.2009.06.014 \n19619998 \n26 Cazzola M , Camiciottoli G , Bonavia M , Gulotta C , Ravazzi A , Alessandrini A , et al (2010 ) Italian real-life experience of omalizumab . Respir Med \n104 : 1410 –1416 . doi: 10.1016/j.rmed.2010.04.013 \n20483574 \n27 Chipps B , Buhl R , Beeh KM , Fox H , Thomas K , Reisner C (2006 ) Improvement in quality of life with omalizumab in patients with severe allergic asthma . Curr Med Res Opin \n22 : 2201 –2208 . doi: 10.1185/030079906X148643 \n17076981 \n28 Abraham I , Alhossan A , Lee C , Kutbi H , MacDonald K (2016) “Real-life” effectiveness of omalizumab in adult patients with severe allergic asthma: systematic review . Allergy \n2016 ; 71 : 593 –610 \ndoi: 10.1111/all.12815 \n26644231 \n29 Alhossan A , Lee C , MacDonald K , Abraham I (2017 ) “Real-life” Effectiveness Studies of Omalizumab in Adult Patients with Severe Allergic Asthma: Meta-analysis . J Allergy Clin Immunol Pract 2017: online\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "12(8)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents; D001249:Asthma; D015415:Biomarkers; D018450:Disease Progression; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D045853:Exhalation; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide; D000069444:Omalizumab; D010342:Patient Acceptance of Health Care; D011241:Prednisone; D011788:Quality of Life; D012720:Severity of Illness Index; D016896:Treatment Outcome", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0183869", "pmc": null, "pmid": "28859150", "pubdate": "2017", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": "20956126;20940232;20483574;25439368;17711616;19619998;18425299;11029340;23471469;11843329;26644231;26200463;11922396;20186367;28351783;15679715;16099149;18445184;10586890;10573240;9877485;8466117;17076981;15817806;22954018;21255035", "title": "The real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma: The ASTERIX Observational study.", "title_normalized": "the real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma the asterix observational study" }	[ { "companynumb": "CA-ROCHE-1996558", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OMALIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103976", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMALIZUMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Asthma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHUTANI M, YANG WH, HEBERT J, TAKACSY FD, STRIL J. THE REAL WORLD EFFECT OF OMALIZUMAB ADD ON THERAPY FOR PATIENTS WITH MODERATE TO SEVERE ALLERGIC ASTHMA: THE ASTERIX OBSERVATIONAL STUDY.. PLOS ONE. 2017;12 (8):-.", "literaturereference_normalized": "the real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma the asterix observational study", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20170921", "receivedate": "20170921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13996223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" } ]
{ "abstract": "The major cardiovascular (CV) adverse effects observed with sipuleucel-T from large multi-institutional clinical trials included thromboembolic events, myocardial infarction, and congestive heart failure in up to 0.3% of patients with CV risk factors. The incidence, outcomes, and mechanisms in real-world clinical settings of these CV adverse effects to date have not been fully elucidated. Our study identified a patient with sipuleucel-T-induced inflammatory cardiomyopathy, which led to the identification of CV adverse effects associated with sipuleucel-T from a large pharmacovigilance database and elucidation of its potential mechanisms.\n\n\n\nUsing the MedDRA term 'cardiac disorders' (System Organ Class level), CV adverse events associated with sipuleucel-T versus all other drugs were reviewed from VigiBase, a large pharmacovigilance database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator. A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. From VigiBase, the total number of CV adverse drug reaction reported with sipuleucel-T was 306 out of a total of 22 980 104 adverse drug reactions in VigiBase on 10/25/2020. MedDRA preferred terms levels were grouped into major CV adverse drug reaction categories where we observed significant reports of myocardial ischaemia, supraventricular tachycardia (particularly atrial fibrillation/atrial flutter), congestive heart failure, and valvular disorders. Myocardial ischemia included acute myocardial infarction (IC025 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with 'cardiac failure congestive' (IC025 1.5), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases considered to be solely due to sipuleucel-T.\n\n\n\nPatients with CV risk factors who are receiving sipuleucel-T may be at higher risk for congestive heart failure, myocardial ischemia, and supraventricular tachycardia. Electrocardiograms during weekly sipuleucel-T infusions and left ventricular function monitoring with echocardiogram should be considered in these patients. Our findings are suggestive of another rare presentation of T-cell-mediated CV toxicity with cancer immunotherapy.", "affiliations": "Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Internal Medicine, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Pathology and Laboratory Medicine, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Pathology and Laboratory Medicine, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Marion L. Shepard Cancer Center, Washington, NC, USA.;Department of Hematology and Oncology, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Pharmacology, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Sorbonne Université, INSERM CIC-1901, AP-HP, Paris, France.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Pharmacology, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Sorbonne Université, INSERM CIC-1901, AP-HP, Paris, France.", "authors": "Moey\|Melissa Y Y\|MYY\|0000-0002-8117-0487;Jiwani\|Rahim A\|RA\|0000-0002-1324-865X;Takeda\|Kotaro\|K\|;Prenshaw\|Karyn\|K\|;Kreeger\|R Wayne\|RW\|;Inzerillo\|John\|J\|;Liles\|Darla K\|DK\|0000-0003-1480-7887;Marcu\|C Bogdan\|CB\|0000-0001-5444-9573;Lebrun-Vignes\|Bénédicte\|B\|0000-0001-6676-5063;Morris\|D Lynn\|DL\|;Ardhanari\|Sivakumar\|S\|;Salem\|Joe-Elie\|JE\|0000-0002-0331-3307", "chemical_list": "D014020:Tissue Extracts; C511774:sipuleucel-T", "country": "England", "delete": false, "doi": "10.1002/ehf2.13400", "fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822\nJohn Wiley and Sons Inc. Hoboken\n\n33938158\n10.1002/ehf2.13400\nEHF213400\nESCHF-20-00821\nShort Communication\nShort Communications\nSipuleucel‐T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database\nSipuleucel‐T associated inflammatory cardiomyopathy\nM.Y.Y. Moey et al.\nMoey Melissa Y.Y. https://orcid.org/0000-0002-8117-0487\n1 [email protected]\n\nJiwani Rahim A. https://orcid.org/0000-0002-1324-865X\n2\nTakeda Kotaro 3\nPrenshaw Karyn 3\nKreeger R. Wayne 1\nInzerillo John 4\nLiles Darla K. https://orcid.org/0000-0003-1480-7887\n5\nMarcu C. Bogdan https://orcid.org/0000-0001-5444-9573\n1\nLebrun‐Vignes Bénédicte https://orcid.org/0000-0001-6676-5063\n6 7\nMorris D. Lynn 1\nArdhanari Sivakumar 1\nSalem Joe‐Elie https://orcid.org/0000-0002-0331-3307\n6 8 9\n1 Department of Cardiovascular Sciences, East Carolina Heart Institute Vidant Medical Center/East Carolina University 115 Heart Drive Greenville NC 27834 USA\n2 Department of Internal Medicine Vidant Medical Center/East Carolina University Greenville NC USA\n3 Department of Pathology and Laboratory Medicine Vidant Medical Center/East Carolina University Greenville NC USA\n4 Marion L. Shepard Cancer Center Washington NC USA\n5 Department of Hematology and Oncology Vidant Medical Center/East Carolina University Greenville NC USA\n6 Department of Pharmacology, Regional Pharmacovigilance Centre Pitié‐Salpêtrière Hospital, Sorbonne Université, INSERM CIC‐1901, AP‐HP Paris France\n7 EA Epiderme‐Epidemiology in Dermatology and Evaluation of Therapeutics Université Paris‐Est Créteil Créteil France\n8 UNICO‐GRECO APHP.Sorbonne Cardio‐Oncology Program Sorbonne Université Paris France\n9 Division of Cardiovascular Medicine, Cardio‐Oncology Program Vanderbilt University Medical Center Nashville TN USA\n* Correspondence to: Melissa Y. Y. Moey, MD MSc, Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC 27834, USA. Tel: +1 252‐744‐4400. Email: [email protected]\n02 5 2021\n8 2021\n8 4 10.1002/ehf2.v8.4 33603368\n25 2 2021\n18 8 2020\n22 4 2021\n© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nAims\n\nThe major cardiovascular (CV) adverse effects observed with sipuleucel‐T from large multi‐institutional clinical trials included thromboembolic events, myocardial infarction, and congestive heart failure in up to 0.3% of patients with CV risk factors. The incidence, outcomes, and mechanisms in real‐world clinical settings of these CV adverse effects to date have not been fully elucidated. Our study identified a patient with sipuleucel‐T‐induced inflammatory cardiomyopathy, which led to the identification of CV adverse effects associated with sipuleucel‐T from a large pharmacovigilance database and elucidation of its potential mechanisms.\n\nMethods and results\n\nUsing the MedDRA term ‘cardiac disorders’ (System Organ Class level), CV adverse events associated with sipuleucel‐T versus all other drugs were reviewed from VigiBase, a large pharmacovigilance database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator. A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. From VigiBase, the total number of CV adverse drug reaction reported with sipuleucel‐T was 306 out of a total of 22 980 104 adverse drug reactions in VigiBase on 10/25/2020. MedDRA preferred terms levels were grouped into major CV adverse drug reaction categories where we observed significant reports of myocardial ischaemia, supraventricular tachycardia (particularly atrial fibrillation/atrial flutter), congestive heart failure, and valvular disorders. Myocardial ischemia included acute myocardial infarction (IC025 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with ‘cardiac failure congestive’ (IC025 1.5), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases considered to be solely due to sipuleucel‐T.\n\nConclusions\n\nPatients with CV risk factors who are receiving sipuleucel‐T may be at higher risk for congestive heart failure, myocardial ischemia, and supraventricular tachycardia. Electrocardiograms during weekly sipuleucel‐T infusions and left ventricular function monitoring with echocardiogram should be considered in these patients. Our findings are suggestive of another rare presentation of T‐cell‐mediated CV toxicity with cancer immunotherapy.\n\nProstate cancer\nImmunotherapy\nSipuleucel‐T\nCardiomyopathy\nCardiotoxicity\nCardio‐oncology\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:28.07.2021\nMoey, M. Y. Y. , Jiwani, R. A. , Takeda, K. , Prenshaw, K. , Kreeger, R. W. , Inzerillo, J. , Liles, D. K. , Marcu, C. B. , Lebrun‐Vignes, B. , Morris, D. L. , Ardhanari, S. , and Salem, J.‐E. (2021) Sipuleucel‐T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database. ESC Heart Failure, 8 : 3360–3368. 10.1002/ehf2.13400.\n==== Body\nBackground\n\nSipuleucel‐T, marketed as Provenge®, is an autologous cellular immunological agent 1 indicated in the treatment of metastatic castration‐resistant prostate cancer (mCRPC). 2 Cardiovascular (CV) toxicities with sipuleucel‐T are uncommon (0.3%). 3 We report the first case of sipuleucel‐T‐induced inflammatory cardiomyopathy and describe the potential mechanisms. Through review of an international pharmacovigilance database, VigiBase, we also identified increased reporting of sipuleucel‐T‐associated CV toxicities.\n\nAims\n\nIn this study, we aimed to elucidate the mechanisms of sipuleucel‐T‐associated cardiomyopathy and to identify CV adverse effects associated with sipuleucel‐T in the real world from VigiBase, the World Health Organization pharmacovigilance database.\n\nClinical case\n\nA 64‐year‐old Caucasian male with well‐controlled hypertension managed with lisinopril 10 mg daily was diagnosed with mCRPC in 2018. He received two doses of subcutaneous degarelix and underwent subsequent transurethral resection of his prostate followed by 6 cycles of docetaxel 75 mg/m2 every 3 weeks along with pegfilgrastim completed 5 months later. He was initiated on enzalutamide 160 mg daily and quarterly intramuscular injections of leuprolide 40 mg shortly after. He had no complications with chemotherapy or hormonal treatment and had significant improvement with prostate‐specific antigen (PSA) < 0.1 ng/mL on subsequent follow‐up (Figure 1 ).\n\nFigure 1 Timeline of patient diagnosis and treatment of metastatic castration‐resistant prostate cancer (mCRPC) and hospitalizations. Our patient was diagnosed with stage IVB prostate cancer in fall of 2018. He was subsequently started on degarelix, which was eventually discontinued due to side effects. He received 6 cycles of docetaxel and started on enzalutamide along with leuprolide. The patient eventually received sipuleucel‐T 8 months following his initial diagnosis for mCRPC. Twenty‐four hours following his second infusion of sipuleucel‐T, he presented to the emergency department with new onset systolic dysfunction (Hospital Admission #1). He underwent coronary angiogram, which did not show obstructive disease. Cardiac magnetic resonance imaging showed late gadolinium enhancement suggestive of an infiltrative disorder. As an outpatient, he was worked up for amyloidosis, which was negative. He was discharged on lisinopril and carvedilol but presented 3 months later with recurrent symptoms and new onset atrial fibrillation (Hospital Admission #2). A myocardial biopsy was obtained during his second admission, which showed chronic myocardial inflammation. The patient was treated medically with lisinopril and carvedilol and continues to tolerate enzalutamide, leuprolide, and denosumab without any recurrent hospitalizations. ADHF, acute decompensated heart failure; AF, atrial fibrillation; HFrEF, heart failure with reduced ejection fraction; NSTEMI, non‐ST elevation myocardial infarction; Q3w, every 3 weeks; Q6 mo, every 6 months; Qd, every day/daily; SPEP, serum protein electrophoresis; SQ, subcutaneous; UPEP, urine protein electrophoresis.\n\nOn 6 months of follow‐up, he was started on sipuleucel‐T every 2 weeks for a total of three infusions. Twenty‐four hours after his second infusion of sipuleucel‐T, he presented with dyspnea and chest pressure. On physical examination, he was afebrile, blood pressure of 145/82 mmHg, and heart rate of 74 b.p.m. with an oxygen saturation of 98% on room air. He had bilateral basilar rales, jugular venous pulse noted to be at least 8 cm with a positive hepatojugular reflex, and a grade 2/6 pansystolic murmur in the apical region without any radiation. He was warm without any lower extremity edema. Electrocardiogram showed new non‐specific intraventricular conduction delay and non‐specific T wave changes in V4 to V6. Troponin I peaked at 0.80 ng/mL (normal <0.03 ng/mL). Brain natriuretic peptide was 1062 pg/mL (normal <200 pg/mL).\n\nA transthoracic echocardiogram revealed a left ventricular ejection fraction (LVEF) of 36%, grade II diastolic dysfunction, grade II mitral regurgitation due to dilated annulus, and mild aortic regurgitation. He received intravenous furosemide 40 mg daily with improvement in symptoms. Left heart catheterization showed 20% non‐obstructive disease in the left anterior descending artery, left circumflex, and right coronary artery. Cardiac magnetic resonance imaging (cMRI) showed biatrial enlargement, moderate mitral regurgitation, and a dilated left ventricular with increased myocardial mass index (116 g/m2, normal range: 42–85 g/m2) and global hypokinesis with an left ventricular ejection fraction (LVEF) of 32%. There was evidence of late gadolinium enhancement with a mottled mid‐wall pattern in the distal septum and the basal inferolateral segment, which was suggestive of a non‐ischemic cardiomyopathy representing myocardial edema or interstitial fibrosis suspicious for chemotherapy‐related cardiomyopathy or infiltrative cardiomyopathy from amyloidosis (Figure 2 ).\n\nFigure 2 Cardiac magnetic resonance imaging. (A) Three‐chamber view. Left panel (magnitude) and right (phase sensitive inversion recovery late gadolinium contrast) study demonstrating increased signal intensity in the inferolateral and distal septal regions. (B) Short‐axis view. There is mottled increased signal intensity on phase sensitive inversion recovery sequence in the distal septal area.\n\nThe patient was discharged with a LifeVest and guideline‐directed medical therapy for heart failure (HF) with reduced ejection fraction, which included carvedilol 3.125 mg twice a day and lisinopril 20 mg daily with follow‐up in the Cardio‐Oncology clinic. The patient received his last sipuleucel‐T infusion 4 weeks after discharge. During this time, given the concern for cardiac amyloidosis based on cMRI, he was worked up as an outpatient with negative fat pad biopsy, bone marrow biopsy, and urine protein electrophoresis. Serum protein electrophoresis showed elevated serum kappa light chains however with normal kappa to lambda ratio. A nuclear study based on transthyretin protein protocol performed was equivocal for cardiac amyloidosis. He presented 4 months later with a 2 week history of orthopnea found to have new‐onset atrial fibrillation and in acute decompensated HF.\n\nAn endomyocardial biopsy (EMB) was subsequently performed due to recurrent HF admission and concern for amyloidosis. The EMB showed several foci of predominant lymphocytic inflammation (Figure 3 ). Given possible immunotherapy‐related myocarditis as observed with immune checkpoint inhibitors (ICIs), 4 specific staining for T‐cell subtypes CD4+ and CD8+ was obtained in addition to a non‐standard of care stain for programmed cell death ligand‐1 (PD‐L1), which is overexpressed in ICI‐related myocarditis. 4 Cardiac amyloidosis was also evaluated with Congo red. Haematoxylin and eosin staining showed several foci of mature lymphocytic infiltration (Figure 3 A and 3 B ) that were positive for both CD4+ and CD8+ (Figure 3 D – 3 F ). PD‐L1 was not detected (Figure 3 F ). Congo red was negative (Figure 3 C ). He was discharged on carvedilol 6.125 mg twice a day, lisinopril 20 mg daily, furosemide 20 mg daily, and apixaban 5 mg twice a day. He did not have any recurrent hospitalizations. A repeat echocardiogram 1 month later showed persistent LVEF depression with an improvement to 45–50% at 6 months of follow‐up.\n\nFigure 3 Endomyocardial biopsy of the right ventricular septum. (A) Haematoxylin and eosin staining of myocardium (low magnification) showing several foci of lymphocyte infiltration. Scale bar, 100 μm. (B) Haematoxylin and eosin staining (high magnification) showing small mature lymphocytes infiltrating in the interstitial area. Scale bar, 50 μm. (C) Congo red staining showing no amyloid deposition. Inset: positive control. Scale bar, 50 μm. (D–F) Immunohistochemistry for CD4 (D), CD8 (E), and programmed cell death ligand‐1 (F). Infiltrating lymphocytes are positive for CD4 or CD8, and negative for programmed cell death ligand‐1. Scale bar, 50 μm.\n\nMethods\n\nWe searched for adverse drug reactions (ADRs) reported in VigiBase (NCT03530215), the World Health Organization database containing individual case safety reports from more than 130 countries since 1967. 5 VigiBase is managed by the Uppsala Monitoring Centre (Uppsala, Sweden). The use of confidential, electronically processed patient data was approved by the French National Commission for Data Protection and Liberties (Commission Nationale de l'Informatique et des Libertés; reference number 1922081). Using the MedDRA term ‘cardiac disorders’ (System Organ Class level), we searched for CV adverse events associated with sipuleucel‐T versus all other drugs in the database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator, which has been previously described. 6 A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. To identify the co‐occurrence of relevant CV‐ADR associated with sipuleucel‐T (IC025 > 0), individual extracted cases were reviewed and the UpSet technique 7 was used to visualize set intersections.\n\nResults\n\nThe total number of CV‐ADR reported with sipuleucel‐T versus all other drugs was 306 and 22 980 104, respectively, on 10/25/2020. There were 18 MedDRA terms of ‘cardiac disorders’ associated with sipuleucel‐T (positive IC025 > 0) (Table 1 ). MedDRA preferred terms levels were grouped into major CV‐ADR categories where there were significant reports of myocardial ischemia, supraventricular tachycardias (SVTs) (atrial fibrillation/atrial flutter), congestive HF (CHF), and valvular disorders. All of these CV‐ADRs were considered severe. Myocardial ischemia included acute myocardial infarction (IC025 = 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with ‘cardiac failure congestive’ (IC025 = 1.4), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases suspected to be solely due to sipuleucel‐T. Other CV‐ADRs were not significantly associated with sipuleucel‐T (Table 1 ). Among the major CV‐ADR categories, these occurred independently with minimal overlap among each major CV‐ADR category. Myocardial ischemia occurred independently in 84.4% (n = 65/77) of all cases, SVT 77.2% (n = 44/57), CHF 75% (n = 36/48), and valvular disorders 62.5% (n = 5/8). SVT was rarely associated with CHF (n = 6/48, 12.5%) and myocardial infarction (n = 6/77, 7.79%) (Figure 4 ).\n\nTable 1 Cardiovascular adverse events (detected as individual case safety reports) reported with sipuleucel‐T in comparison with the full VigiBase database on 10/25/2020\n\nCardiac adverse event\tMedDRA preferred term level\tICSR with sipuleucel‐T (n total = 3943)\tICSR in full database (n = 22 980 104)\tIC (IC025)\tSerious adverse events\tFatal events\tSuspected due to sipuleucel‐T only\t\nMyocardial ischaemia\tAcute myocardial infarction\t26\t17 700\t2.9 (2.3)\t26\t4\t23\t\nCoronary artery occlusion\t8\t9723\t2.0 (0.8)\t8\t2\t7\t\nMyocardial infarction\t42\t143 746\t0.8 (0.3)\t42\t13\t42\t\nCoronary artery disease\t10\t25 890\t1.1 (0.1)\t10\t0\t9\t\nSupraventricular tachycardia\tAtrial fibrillation\t49\t60 507\t2.2 (1.8)\t48\t10\t41\t\nAtrial flutter\t6\t5136\t2.2 (0.9)\t6\t1\t5\t\nCongestive heart failure\tCardiac failure congestive\t43\t67 656\t1.8 (1.4)\t43\t11\t42\t\nDilatation ventricular\t4\t1161\t2.7 (0.9)\t4\t1\t3\t\nDiastolic dysfunction\t4\t1531\t2.6 (0.8)\t4\t0\t3\t\nValvular disorders\tTricuspid valve incompetence\t5\t5017\t2.0 (0.5)\t5\t1\t5\t\nMitral valve incompetence\t6\t9522\t1.6 (0.2)\t6\t1\t4\t\nMiscellaneous\tExtrasystoles\t7\t8639\t1.9 (0.7)\t6\t0\t5\t\nTachycardia\t50\t137 211\t1.1 (0.6)\t36\t4\t44\t\nVentricular extrasystoles\t6\t7010\t1.9 (0.6)\t6\t1\t6\t\nLeft ventricular hypertrophy\t4\t2659\t2.2 (0.5)\t4\t1\t4\t\nCardiac disorder\t20\t55 766\t1.0 (0.3)\t9\t4\t20\t\nCardiomegaly\t6\t8828\t1.7 (0.3)\t6\t0\t4\t\nSinus tachycardia\t6\t9899\t1.6 (0.2)\t6\t1\t4\t\nIC, information component; ICSR, individual case safety report.\n\nAn IC025 > 0 (information component 95% credibility interval lower end) is considered significant.\n\nFigure 4 Intersection of major cardiovascular adverse drug reaction (CV‐ADR) categories associated with sipuleucel‐T. Myocardial ischemia occurred independently 84.4% (n = 65/77) of all cases, supraventricular tachycardia (SVT) 77.2% (n = 44/57), congestive heart failure (CHF) 75% (n = 36/48), and valvular disorders 62.5% (n = 5/8). SVT was rarely associated with CHF (n = 6/48, 12.5%) and myocardial infarction (n = 6/77, 7.79%).\n\nDiscussion\n\nWe describe the first reported phenomenon of a T‐cell‐mediated sipuleucel‐T‐induced cardiomyopathy. This is further corroborated by our pharmacovigilance analysis that revealed an over‐reporting of CHF with sipuleucel‐T with ~15% fatality.\n\nAlthough CV toxicities from sipuleucel‐T were uncommon among clinical trials, 3 we demonstrate through VigiBase that there was significant over‐reporting of myocardial ischemia, SVT, and CHF with sipuleucel‐T versus all other drugs. While reports from VigiBase are non‐homogeneous with the inability to definitively verify the cases with clinical, laboratory, or radiological tests, we suspect that these CV‐ADRs may have been one of the manifestations of an inflammatory‐mediated cardiomyopathy. 8 Our observation of lymphocytic inflammation on myocardial biopsy suggests that sipuleucel‐T invoked an inflammatory cascade that resulted in a T‐cell‐mediated cardiomyopathy with similar features to observed cases of immune‐related CV toxicities such as with influenza vaccination 9 , 10 and ICIs. 4\n\nIn fact, preclinical production studies of sipuleucel‐T demonstrated an immune priming response followed by immune boosting with subsequent infusions, similar to classic vaccine‐mediated cellular and humoral responses. 11 Antigen‐presenting cells, detected by CD54, were significantly up‐regulated after the first dose with the most robust response at week 4, along with antigen‐presenting cell activation‐associated cytokines, which is followed by T‐cell activation‐associated cytokines in the second and third infusion preparations. 11 Particularly, from peripheral blood samples obtained from patients receiving sipuleucel‐T, both T‐cell helper 1 (interferon and tumour necrosis factor‐α) and 2 [interleukin (IL)‐5 and IL‐13]‐specific cytokines were elevated, supporting the mechanism of sipuleucel‐T‐mediated cellular and humoral responses. Acting in concert with interferon and tumour necrosis factor‐α, an increase in IL‐17 levels was also observed, which has been implicated in the pathophysiology of autoimmune diseases. 12 Specific responses measured by anti‐PA2024 and anti‐PAP antibody titres were sustained at least until week 26. 11 This may have resulted in cytokine cascade, 9 , 10 which resulted in T‐cell recruitment and myocardial injury in our patient.\n\nUnique to our case was the observation of CD4+ and CD8+ T cells within focal inflammatory areas on myocardial biopsy. Notably, sipuleucel‐T increases the frequency of CD4+ and CD8+ T cells within prostate tissue 2 to 3 weeks after treatment, particularly at the tumour margin. 13 Whether sipuleucel‐T may induce a generalized inflammatory response that can affect additional organs has not yet been reported in preclinical sipuleucel‐T‐treated animal models. 13 These preclinical findings of an increased immune response at week 2 with the most robust response at week 4 are consistent with the timeline to development of our patient's inflammatory cardiomyopathy, further corroborating the high likelihood of sipuleucel‐T exposure as the suspected cause.\n\nWe did not observe an increased expression of PD‐L1 in the myocardium as previously demonstrated in ICI‐related myocarditis. 4 This is likely due to a variation in the mechanism of action whereby ICI exhibits a generalized immune blockade whereas sipuleucel‐T induces a destruction specific to prostate cancer cells. However, the phenomenon of ‘antigen spread’ with sipuleucel‐T where additional prostate cancer‐associated tumour antigens involved in PSA processing and oncologic downstream signalling were targeted has also been observed. 14 We suspect that cross‐reactivity and/or shared antigen recognition within the myocardium by sipuleucel‐T is likely low, however possible in pro‐inflammatory environments such as patients with CV risk factors. 15\n\nOur patient had LVEF recovery within 6 months on guideline‐directed medical therapy only. This suggests that the immune‐mediated mechanisms were likely transient, with reversion to a balanced non‐inflammatory environment following completion of sipuleucel‐T treatment. Nonetheless, our patient experienced a severe reaction reflecting our pharmacovigilance results in which approximately 15% of patients with spiuleucel‐T‐associated CHF associated suffered fatal outcomes. While our patient was concomitantly receiving androgen‐deprivation therapy (ADT) with enzalutamide and leuprolide, the likelihood of ADT resulting in cardiomyopathy was low in the differential. Cardiotoxicities reported with ADT include cardiometabolic disturbances (hypertension, hyperglycemia, and hyperlipidemia) and risk of arrhythmias from prolonged QTc 16 and are generally not associated risk of HF; in clinical trials, HF was reported to be <1%. 17 , 18 Docetaxel has also not been associated with HF despite prolonged use. 19 Our patient tolerated ADT and docetaxel for several months but developed acute onset of symptoms with sipuleucel‐T, correlating with the timeline of the immune modulating mechanism of sipuleucel‐T and potential crosstalk between pathways making sipuleucel‐T the most plausible culprit of our patient's inflammatory cardiomyopathy.\n\nIn comparison with the familiarity of cardiotoxicities associated with anthracyclines and anti‐human epidermal growth factor receptor (HER2) therapy, prostate cancer therapy‐induced cardiac adverse events are underrecognized. There have been concerns regarding adequate reporting and potential under recognition of adverse cardiac events with prostate cancer therapies as the studies were not designed to detect cardiotoxicities. 20 Therefore, we encourage consideration of monitoring in patients with CV risk factors with serial electrocardiograms during weekly infusions and obtaining a baseline echocardiogram in patients receiving sipuleucel‐T. Additional studies investigating the complex immune‐mediated mechanisms in patients receiving immunotherapy and optimal management to avoid off‐target organ inflammation without affecting the salutary effects of immunotherapy are highly warranted.\n\nLimitations\n\nOur study is not without limitations. As there are no current guidelines regarding obtaining baseline cardiac diagnostic testing prior to initiation of prostate cancer treatment, our patient did not have a baseline echocardiogram for comparison. The patient did not have any cardiac symptoms or complaints that would have suggested baseline systolic or valvular dysfunction; therefore, it is assumed that his baseline cardiac function was normal prior to and during his non‐immunotherapy treatment for mCRPC. Another limitation of our study was the lack of viral genome data from EMB. The patient did not have any viral or infectious symptoms at the time of his admission in addition to negative blood cultures and respiratory viral panel; an infectious or viral‐associated cardiomyopathy was very low in the differential. In addition, limitations with VigiBase reporting are voluntary, and thus, not all data fields are included in every report, and quality might be variable.\n\nConflict of interest\n\nNone declared.\n\nSupporting information\n\nFigure S1. Supporting Information.\n\nClick here for additional data file.\n\nFigure S2. Supporting Information.\n\nClick here for additional data file.\n\nAcknowledgements\n\nThe supplied data from VigiBase® come from various sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the World Health Organization.\n==== Refs\nReferences\n\n1 Cheever M , Higano C . PROVENGE (sipuleucel‐T) in prostate cancer: the first FDA‐approved therapeutic cancer vaccine. Clin Cancer Res 2011; 17 : 3520–3526.21471425\n2 Kantoff PW , Higano CS , Shore ND , Berger ER , Small EJ , Penson DF , Redfern CH , Ferrari AC , Dreicer R , Sims RB , Xu Y , Frohlich MW , Schellhammer PF . Sipuleucel‐T immunotherapy for castration‐resistant prostate cancer. N Engl J Med 2010; 363 : 411–422.20818862\n3 Higano CS , Armstrong AJ , Sartor AO , Vogelzang NJ , Kantoff PW , McLeod DG , Pieczonka CM , Penson DF , Shore ND , Vacirca J , Concepcion RS , Tutrone RF , Nordquist LT , Quinn DI , Kassabian V , Scholz MC , Harmon M , Tyler RC , Chang NN , Tang H , Cooperberg MR . Real‐world outcomes of sipuleucel‐T treatment in PROCEED, a prospective registry of men with metastatic castration‐resistant prostate cancer. Cancer 2019; 125 : 4172–4180.31483485\n4 Johnson DB , Balko JM , Compton ML , Chalkias S , Gorham J , Xu Y , Hicks M , Puzanov I , Alexander MR , Bloomer TL , Becker JR , Slosky DA , Phillips EJ , Pilkinton MA , Craig‐Owens L , Kola N , Plautz G , Reshef DS , Deutsch JS , Deering RP , Olenchock BA , Lichtman AH , Roden DM , Seidman CE , Koralnik IJ , Seidman JG , Hoffman RD , Taube JM , Diaz LA Jr , Anders RA , Sosman JA , Moslehi JJ . Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016; 375 : 1749–1755.27806233\n5 Lindquist M . VigiBase, the WHO global ICSR database system: basic facts. Drug Inf J 2008; 42 : 409–419.\n6 Salem JE , Manouchehri A , Moey M , Lebrun‐Vignes B , Bastarache L , Pariente A , Gobert A , Spano JP , Balko JM , Bonaca MP , Roden DM , Johnson DB , Moslehi JJ . Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018; 19 : 1579–1589.30442497\n7 Lex A , Gehlenborg N , Strobelt H , Vuillemot R , Pfister H . UpSet: visualization of intersecting sets. IEEE Trans Vis Comput Graph 2014; 20 : 1983–1992.26356912\n8 Lyon AR , Yousaf N , Battisti NML , Moslehi J , Larkin J . Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol 2018; 19 : e447–e458.30191849\n9 Saraiya N , Singh S , Corpuz M . Fatal influenza myocarditis with incessant ventricular tachycardia. BMJ Case Rep CP 2019; 12 : e228201.\n10 Kim YJ , Bae JI , Ryoo SM , Kim WY . Acute fulminant myocarditis following influenza vaccination requiring extracorporeal membrane oxygenation. Acute Crit Care 2019; 34 : 165–169.31723923\n11 Sheikh NA , Petrylak D , Kantoff PW , dela Rosa C , Stewart FP , Kuan LY , Whitmore JB , Trager JB , Poehlein CH , Frohlich MW , Urdal DL . Sipuleucel‐T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration‐resistant prostate cancer. Cancer Immunol Immunother 2013; 62 : 137–147.22865266\n12 Kuwabara T , Ishikawa F , Kondo M , Kakiuchi T . The role of IL‐17 and related cytokines in inflammatory autoimmune diseases. Mediators Inflamm 2017; 2017 : 3908061.28316374\n13 Laus R , Yang DM , Ruegg CL , Shapero MH , Slagle PH , Small EJ , Burch P , Valone FH . Dendritic cell immunotherapy of prostate cancer: preclinical models and early clinical experience. Cancer Res Ther Control 2001; 11 : 1–10.\n14 GuhaThakurta D , Sheikh NA , Fan LQ , Kandadi H , Meagher TC , Hall SJ , Kantoff PW , Higano CS , Small EJ , Gardner TA , Bailey K , Vu T , DeVries T , Whitmore JB , Frohlich MW , Trager JB , Drake CG . Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel‐T and its association with improved clinical outcome. Clin Cancer Res 2015; 21 : 3619–3630.25649018\n15 Willerson JT , Ridker PM . Inflammation as a cardiovascular risk factor. Circulation 2004; 109 : II2–II10.15173056\n16 Salem JE , Yang T , Moslehi JJ , Waintraub X , Gandjbakhch E , Bachelot A , Hidden‐Lucet F , Hulot JS , Knollmann BC , Lebrun‐Vignes B , Funck‐Brentano C , Glazer AM , Roden DM . Androgenic effects on ventricular repolarization: a translational study from the international pharmacovigilance database to iPSC‐cardiomyocytes. Circulation 2019; 140 : 1070–1080.31378084\n17 Scher HI , Fizazi K , Saad F , Taplin ME , Sternberg CN , Miller K , de Wit R , Mulders P , Chi KN , Shore ND , Armstrong AJ , Flaig TW , Fléchon A , Mainwaring P , Fleming M , Hainsworth JD , Hirmand M , Selby B , Seely L , de Bono JS . Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367 : 1187–1197.22894553\n18 Beer TM , Armstrong AJ , Rathkopf DE , Loriot Y , Sternberg CN , Higano CS , Iversen P , Bhattacharya S , Carles J , Chowdhury S , Davis ID . Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371 : 424–433.24881730\n19 Zamorano JL , Lancellotti P , Rodriguez Muñoz D , Aboyans V , Asteggiano R , Galderisi M , Habib G , Lenihan DJ , Lip GYH , Lyon AR , Fernandez TL , Mohty D , Piepoli MF , Tamargo J , Torbicki A , Suter TM , ESC Scientific Document Group . 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37 : 2768–2801.27567406\n20 Witteles RM , Telli M . Underestimating cardiac toxicity in cancer trials: lessons learned? J Clin Oncol 2012; 30 : 1916–1918.22454419\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2055-5822", "issue": "8(4)", "journal": "ESC heart failure", "keywords": "Cardio-oncology; Cardiomyopathy; Cardiotoxicity; Immunotherapy; Prostate cancer; Sipuleucel-T", "medline_ta": "ESC Heart Fail", "mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D001499:Bayes Theorem; D006801:Humans; D009205:Myocarditis; D060735:Pharmacovigilance; D014020:Tissue Extracts", "nlm_unique_id": "101669191", "other_id": null, "pages": "3360-3368", "pmc": null, "pmid": "33938158", "pubdate": "2021-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25649018;15173056;28316374;31483485;22454419;27806233;31266755;22865266;26356912;21471425;30442497;30191849;31378084;27567406;24881730;33938158;22894553;31723923;20818862", "title": "Sipuleucel-T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database.", "title_normalized": "sipuleucel t associated inflammatory cardiomyopathy a case report and observations from a large pharmacovigilance database" }	[ { "companynumb": "US-TOLMAR, INC.-22US032427", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "021731", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Subcutaneous injection", "drugdosagetext": "45 MILLIGRAM, Q 6 MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hormone-refractory prostate cancer", "drugintervaldosagedefinition": "802", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20181226", "drugstartdateformat": "102", 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"SIPULEUCEL-T" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIPULEUCEL-T" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190624", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIPULEUCEL-T" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIPULEUCEL-T" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190722", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIPULEUCEL-T" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENZALUTAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hormone-refractory prostate cancer", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20181127", "drugstartdateformat": "102", "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENZALUTAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MILLIGRAM PER CUBIC METRE, Q 3 WEEK", "drugenddate": "20190307", "drugenddateformat": "102", "drugindication": "Hormone-refractory prostate cancer", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20181127", 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"drugtreatmentdurationunit": null, "medicinalproduct": "DENOSUMAB" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac failure acute", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20181226" } }, "primarysource": { "literaturereference": "Moey M.Y.Y., Jiwani R.A., Takeda K., Prenshaw K., Kreeger R.W., Inzerillo J., Liles D.K., Marcu C.B., Lebrun-Vignes B., Morris D.L., Ardhanari S., Salem J.-E.. Sipuleucel-T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database. ESC Heart Failure (2021) 8:4 (3360-3368). Date of Publication: 1 Aug 2021. 2021;4:3360 - 3368", "literaturereference_normalized": "sipuleucel t associated inflammatory cardiomyopathy a case report and observations from a large pharmacovigilance database", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220118", "receivedate": "20220118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20343958, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220423" } ]
{ "abstract": "We report a case of breast cancer in a 58-year-old female patient. In 2005, she was hospitalized for therapy of left breast cancer. The tumor observed was accompanied by invasion of the skin and ribs. At the same time, multiple liver and bone metastases were also observed(solid tubular adenocarcinoma, ER(+), PgR(±), HER2(3+), T4NxM1, stage IV). She was started on radiation therapy and chemotherapy(paclitaxel+trastuzumab). While the liver and bone metastases remained unchanged, the primary focus became noticeably smaller. In the course of follow-up visits, we began to administer her paclitaxel biweekly. This treatment, however, worsened her liver metastases and led us to switch to combination chemotherapy with vinorelbine and capecitabine. After 6 courses of the therapy, her liver metastases disappeared and her tumor marker levels became normal. The combination chemotherapy was continued for 1 year and then followed by 18 months of chemotherapy with capecitabine alone until recurrence of liver metastases was observed. Capecitabine along with cyclophosphamide was orally administered, bringing her tumor marker levels down to the normal range again. After approximately 6 years from the start of treatment, the patient is still alive.", "affiliations": "Dept. of Surgery, Takarazuka City Hospital, Japan.", "authors": "Yamazaki\|Junya\|J\|;Kou\|Toshimori\|T\|;Sakakura\|Chohei\|C\|;Oguro\|Atsushi\|A\|;Nakagawa\|Noboru\|N\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "39(3)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D001706:Biopsy; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008875:Middle Aged; D012074:Remission Induction; D014456:Ulcer", "nlm_unique_id": "7810034", "other_id": null, "pages": "437-9", "pmc": null, "pmid": "22421775", "pubdate": "2012-03", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy.", "title_normalized": "a case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy" }	[ { "companynumb": "JP-HQ SPECIALTY-JP-2016INT000263", "fulfillexpeditecriteria": "1", "occurcountry": "JP", 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A CASE OF BREAST CANCER WITH LARGE CANCER ULCER AND MULTIPLE BONE AND LIVER METASTASIS RESPONDING TO COMBINATION THERAPY OF RADIATION AND CHEMOTHERAPY. 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A CASE OF BREAST CANCER WITH LARGE CANCER ULCER AND MULTIPLE BONE AND LIVER METASTASIS RESPONDING TO COMBINATION THERAPY OF RADIATION AND CHEMOTHERAPY. [JAPANESE]. GAN-TO-KAGAKU-RYOHO 2012?39(3):437-439.", "literaturereference_normalized": "a case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12191981, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "BACKGROUND\nCancer is the second leading cause of death of women during the reproductive years, and its occurrence in pregnancy is between 0.07% and 0.1%.\n\n\nMETHODS\nTo analyze the effect of cancer on pregnancy, we compared 21 pregnancies occurring during 30 years in women who received chemotherapy for their cancer with a control group matched for maternal age and composed of women not exposed to known teratogens or reproductive risks during pregnancy.\n\n\nRESULTS\nOf 13 women exposed to chemotherapy during the first trimester, two of five whose pregnancies continued to term had major malformations in their infants, four had spontaneous abortions, and four had therapeutic abortions. Of four women with second-trimester exposure to chemotherapy, two had normal live births, one had a stillbirth, and one had a therapeutic abortion. All four pregnancies exposed to chemotherapy during the third trimester resulted in healthy live births. Infants exposed to chemotherapy had statistically significantly lower birth weights than their matched controls (2227 +/- 558 g vs 3519 +/- 272 g, P less than .001), due to both significantly lower gestational age and substantial intrauterine growth retardation (P less than .01). The trend for higher rate of stillbirth (1/11) agrees well with 10 stillbirths among all women with cancer in pregnancy without and with chemotherapy who gave birth (n = 223), when compared with the population of Ontario (P less than .0005).\n\n\nCONCLUSIONS\nThis study confirms the increased likelihood of spontaneous abortions and major birth defects when chemotherapy is used during embryogenesis, whereas such a risk is not apparent beyond the first trimester. Because of the higher risk of stillbirth and intrauterine growth retardation, women with cancer should be monitored closely by a high-risk obstetric unit to define the optimal time of delivery.", "affiliations": "Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.", "authors": "Zemlickis\|D\|D\|;Lishner\|M\|M\|;Degendorfer\|P\|P\|;Panzarella\|T\|T\|;Sutcliffe\|S B\|SB\|;Koren\|G\|G\|", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-9926", "issue": "152(3)", "journal": "Archives of internal medicine", "keywords": null, "medline_ta": "Arch Intern Med", "mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D000013:Congenital Abnormalities; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D009864:Ontario; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third", "nlm_unique_id": "0372440", "other_id": null, "pages": "573-6", "pmc": null, "pmid": "1546920", "pubdate": "1992-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Fetal outcome after in utero exposure to cancer chemotherapy.", "title_normalized": "fetal outcome after in utero exposure to cancer chemotherapy" }	[ { "companynumb": "CA-PFIZER INC-2019281858", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071868", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stillbirth", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZEMLICKIS, D.. 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"qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190703", "receivedate": "20190703", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16521596, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-PFIZER INC-2019281857", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROCARBAZINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ZEMLICKIS, D.. FETAL OUTCOME AFTER IN UTERO EXPOSURE TO CANCER CHEMOTHERAPY. ARCH INTERN MED. 1992?152:573-576", "literaturereference_normalized": "fetal outcome after in utero exposure to cancer chemotherapy", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190708", "receivedate": "20190708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16541085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "CA-PFIZER INC-2019281855", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROCARBAZINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROCARBAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MECHLORETHAMINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MECHLORETHAMINE HYDROCHLORIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZEMLICKIS, D.. FETAL OUTCOME AFTER IN UTERO EXPOSURE TO CANCER CHEMOTHERAPY. ARCH INTERN MED. 1992?152:573-576", "literaturereference_normalized": "fetal outcome after in utero exposure to cancer chemotherapy", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190708", "receivedate": "20190708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16541361, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "BACKGROUND\nDementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65 years and above. More effective ways to manage dementia symptoms are needed because current treatment options (antidepressants and antipsychotics) can be ineffective and are associated with substantial side effects, including increased rate of mortality. Cannabinoid-based medicine (CBM) has shown an ability to inhibit some symptoms associated with dementia, and the adverse effects are often minimal; yet, little research has explored the use of CBM among this population.\n\n\nOBJECTIVE\nTo monitor the safety of a purified dose of CBM oil (3:2 delta-9-tetrahydrocannabinol:cannabidiol) on behaviour symptoms, quality of life and discomfort caused by pain.\n\n\nMETHODS\nWe will carry out an 18-week, randomised, double-blind crossover trial that consists of a 2-week eligibility period, two 6-week treatment cycles, and two 2-week washout periods (between both cycles and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups and will receive a dose of either CBM oil or placebo for the first treatment cycle and the opposite medication for the second. Data will be collected using the Neuropsychiatric Inventory Questionnaire, the Cohen-Mansfield Agitation Inventory, the Quality of Life in Alzheimer's Disease questionnaire, and the Abbey Pain Scale on seven occasions. These will be completed by the participants, aged-care staff, and nominated next of kin or family members. The participants' heart rate and blood pressure will be monitored weekly, and their body composition and weight will be monitored fortnightly by a research nurse, to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions of CBM and to inform proposed focus groups consisting of the aged-care staff and next of kin.\n\n\nCONCLUSIONS\nThe study design has been informed by medical professionals and key stakeholders, including those working in the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.\n\n\nBACKGROUND\nAustralian New Zealand Clinical Trials Registry, ACTRN12619000474156. Registered on 21 March 2019.", "affiliations": "Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia. [email protected].;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.;Emerald Clinics, Perth, WA, Australia.;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.", "authors": "Timler\|Amanda\|A\|http://orcid.org/0000-0003-2619-5937;Bulsara\|Caroline\|C\|;Bulsara\|Max\|M\|;Vickery\|Alistair\|A\|;Smith\|Jill\|J\|;Codde\|Jim\|J\|", "chemical_list": "D002186:Cannabinoids; D064086:Medical Marijuana; D010938:Plant Oils", "country": "England", "delete": false, "doi": "10.1186/s13063-020-4085-x", "fulltext": "\n==== Front\nTrialsTrialsTrials1745-6215BioMed Central London 408510.1186/s13063-020-4085-xStudy ProtocolUse of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial http://orcid.org/0000-0003-2619-5937Timler Amanda [email protected] 1Bulsara Caroline 1Bulsara Max 1Vickery Alistair 2Smith Jill 1Codde Jim 11 0000 0004 0402 6494grid.266886.4Institute for Health Research, University of Notre Dame Australia, Perth, WA Australia 2 Emerald Clinics, Perth, WA Australia 14 2 2020 14 2 2020 2020 21 18816 5 2019 18 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65 years and above. More effective ways to manage dementia symptoms are needed because current treatment options (antidepressants and antipsychotics) can be ineffective and are associated with substantial side effects, including increased rate of mortality. Cannabinoid-based medicine (CBM) has shown an ability to inhibit some symptoms associated with dementia, and the adverse effects are often minimal; yet, little research has explored the use of CBM among this population.\n\nAim\nTo monitor the safety of a purified dose of CBM oil (3:2 delta-9-tetrahydrocannabinol:cannabidiol) on behaviour symptoms, quality of life and discomfort caused by pain.\n\nMethods/design\nWe will carry out an 18-week, randomised, double-blind crossover trial that consists of a 2-week eligibility period, two 6-week treatment cycles, and two 2-week washout periods (between both cycles and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups and will receive a dose of either CBM oil or placebo for the first treatment cycle and the opposite medication for the second. Data will be collected using the Neuropsychiatric Inventory Questionnaire, the Cohen-Mansfield Agitation Inventory, the Quality of Life in Alzheimer’s Disease questionnaire, and the Abbey Pain Scale on seven occasions. These will be completed by the participants, aged-care staff, and nominated next of kin or family members. The participants’ heart rate and blood pressure will be monitored weekly, and their body composition and weight will be monitored fortnightly by a research nurse, to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions of CBM and to inform proposed focus groups consisting of the aged-care staff and next of kin.\n\nDiscussion\nThe study design has been informed by medical professionals and key stakeholders, including those working in the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.\n\nTrial registration\nAustralian New Zealand Clinical Trials Registry, ACTRN12619000474156. Registered on 21 March 2019\n\nKeywords\nDementiaMedicinal cannabisQuality of lifePainBehavioural and neuropsychiatric symptoms of dementia (BPSD)Crossover trialMGC Pharmaceuticals issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDementia is a collection of symptoms that progressively reduces the cognitive and functional ability of the brain [1] and affects memory, intellect, rationality, social skills and physical functioning [2]. The symptoms associated with dementia present themselves in a variety of ways and can include depression, frustration, clinginess, forgetfulness, wandering, sexual aggression, hoarding, sleep disturbances and ‘the sundowner effect’ (increased manifestations of challenging behaviours at the end of the day [3]). Severe cognitive fluctuations in patients with dementia have been associated with an individual’s impaired ability to engage in activities of daily living, including social interactions and poorer quality of life (QOL) [4]. The slow progression and degeneration of dementia require that the affected individual receive additional support and assistance to remain at home or ultimately admission into residential aged-care facilities with 24-h care.\n\nDementia is the second leading burden of disability among Australians aged 65 years and older, and the burden of disease is expected to increase exponentially over the next 30 years [5]. Alzheimer’s disease is the most common cause of dementia and affects approximately 50–70% of the elderly with dementia. Pharmacological management of behavioural and physical symptoms of dementia is currently the most common treatment option, and many are prescribed medications such as off-label antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, and antidepressants to mask and alleviate the array of dementia symptoms [6, 7]. Medications such as aripiprazole, olanzapine, risperidone and memantine have been shown to reduce troublesome behaviours [8], although unclear guidelines are often provided for administration [2, 7]. This results in polypharmacy and its inherent risks, with numerous medications being prescribed for a longer duration than recommended [9]. Many of these medications lead to a number of substantial side effects [10], including increased rate of stroke and mortality [11].\n\nCannabinoid-based medicines (CBMs) have been shown to improve dementia symptoms such as aggression and agitation [12, 13], and they appear to be safer to prescribe than other pharmacotherapies [3] because the adverse effects are often minimal [14]. For example, Weier and Hall [15] found sedation to be the only adverse effect among patients with dementia prescribed either cannabinoids or pharmacotherapies. While periods of euphoria, somnolence and tiredness were observed among those prescribed dronabinol, a synthetically derived delta-9-tetrahydrocannabinol (THC) [16], there were only a small number of adverse events (6 of 98) related to the administration of the synthetic THC similar to those manifested by the placebo [14, 17]. However, well-designed, randomised, double-blind, placebo-controlled trials need to be completed to understand the most efficacious formulation, safety profile, drug–drug interactions and true effect to determine the place of CBM in dementia [18, 19], allowing greater generalisability of these outcomes [20].\n\nA range of CBMs (synthetic compounds such as dronabinol or nabilone or pure cannabinols) are available; however, the combination of cannabidiol (CBD; the non-psychoactive compound) and THC (the psychoactive compound) [21] appear to be most effective, because both compounds improve psychomotor activity, mood, sleep–wake cycles and eating behaviours [14, 22, 23]. THC and CBD interact with the endogenous cannabinoid systems CB1 and CB2 receptors [19, 23, 24], producing symbiotic neuroprotective effects. For example, in pre-clinical trials, THC is found to be a partial CB1 antagonist and improves immune function [25], encourages amyloidogenesis [14, 22, 23, 26, 27], reduces neuropsychiatric symptoms, reduces pain sensation [28], stimulates appetite [21–23, 29], and inhibits acetylcholinesterase, similarly to cholinesterase inhibitors such as donepezil [30]. CBD is an inverse CB1 agonist [31] that promotes neurogenesis and vasodilation within the brain; increases neuronal plasticity and cerebral blood flow [32]; prevents cell destruction; and has anti-inflammatory (neuroinflammation and peripheral inflammation), analgesic, anticonvulsant and anxiolytic properties [25]. CBD is an important compound because it reverses the negative cognitive consequences and ameliorates the psychoactive properties of THC [21–23, 29].\n\nStudies assessing the safety and efficiency of CBMs have shown many benefits among other neurodegenerative diseases, such as Parkinson’s disease [33, 34], epilepsy, post-traumatic stress disorder [18, 35], anxiety [12], and spasticity due to multiple sclerosis [36], with the use of CBM reducing benzodiazepine prescriptions by 45% [37]. However, only a handful of studies have investigated the use of CBM in patients with dementia [13, 14, 23]. Recently, an observational study monitored the use of a CBM medication over a 2-month period among ten females with severe dementia and found a 40% reduction in behavioural problems and 50% reduction in rigidity [38].\n\nThe pharmacodynamics and pharmacokinetics of THC (weeks 1–6, 0.75 mg; weeks 7–12, 1.5 mg) administered to ten participants with dementia was safe and well tolerated [14]. Administration of THC 2.5 mg in 11 patients with dementia demonstrated positive effects on mental state; dementia severity; and behavioural symptoms such as delusions, irritability, sleep and caregiver distress [23]. Studies reporting the use of dronabinol (2.5 mg daily) found improvements in anorexia and body weight, as well as less disturbed behaviours [16] such as agitation and motor behaviours, with no adverse effects observed [39]. Retrospective observations of dronabinol administration among 40 hospitalised patients indicated improvements in agitation and aggression, sleep duration, and meal consumption [13]. Two independent case studies monitoring the effects of nabilone (maximum dose 0.5 mg twice daily for 6 weeks) among elders with dementia found improvements in severe agitation and aggression [40], psychomotor activity, and smiling, as well as positive experiences among family members [41]. No changes in the number of falls or in balance (with eyes open) were reported among 18 participants administered 1.5 mg of oral THC twice daily [42], with recommendations suggesting higher doses (THC 1.5 mg three times daily), and longer study durations (great than 3 weeks) are needed to understand the true effects on behavioural symptoms, including QOL and activities of daily living [43]. Therefore, further research in this area is needed because many beneficial outcomes have been reported, although dosing, samples size, patient cohort (2–50 participants) and outcomes have varied in what are generally small studies with poor experimental designs.\n\nAims\nThe primary aim of the present study will be to see if a purified CBM oil is safe and improves behavioural and neuropsychiatric symptoms of dementia (BPSD). In addition, two secondary aims of this study will include examining QOL and discomfort caused by pain among patients with dementia receiving CBM oil.\n\nMethods and general study design\nThis study has received approval from the Human Ethics Research Committee at the University of Notre Dame Australia. The study will use a parallel mixed methods design. The research methodology for this study is a phase II, randomised, placebo-controlled crossover trial. The design will include a 2-week eligibility (assessment) period, two 6-week-treatment cycles to allow each participant to take part in both the control and treatment cycles, and two 2-week washout periods (one between both treatment cycles and the other after the second treatment cycle). The 6-week treatment cycles have been selected on the basis of safety, pharmacodynamics, and pharmacokinetics as reported by Ahmed et al. [14], and a 2-week washout period has been shown to be safe and an appropriate length of time for cannabis to metabolise in older individuals [44].\n\nIn addition, residential aged-care staff and next of kin perceptions towards the use of CBM oil will be evaluated via surveys administered prior to and upon completion of the study. At the end of the second treatment cycle, the residential aged-care staff and family members will be asked to participate in a follow-up focus group to gather more in-depth information regarding individuals’ perceptions before and after the administration of CBM. Each participant will be in the trial for approximately 4 months (18 weeks), but the duration of the study will last over 12 months in order to recruit participants from a number of aged-care facilities.\n\nParticipants and setting\nParticipants will be recruited through residential aged-care facilities. Residential aged-care facilities within Australia are government-funded organisations that provide additional support for families who may have a family member with dementia, whereby many move from their residential homes into a residential aged-care facility so that they can be monitored and provided with additional care. PASS2019 power analysis and sample size software (ncss.com/software/pass; NCSS, Kaysville, UT, USA) was used to derive the sample size. The Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) is the primary outcome measure. Total sample size for a 2 × 2 crossover design assuming a two-sided t test to detect a mean difference of 6 on the NPI-NH scale with a standard deviation of 13 (for the difference) is 40 for a power of 80% and significance level of 5%. Fifty participants will be recruited to allow for a 20% attrition rate. Participants will be eligible to participate if they live in a residential aged-care facility, are aged 65 years or older, have a diagnosis of mild dementia (indicated by a score ≥ 20 on the Mini Mental State Examination [MMSE]), are able to speak English, are known as compliant with taking medication, are not bedridden, and are able to provide informed consent. Participants will be excluded if they have certain health conditions, such as frontotemporal or Lewy body dementia; have other comorbidities, such as epilepsy, anorexia nervosa, comorbid psychiatric conditions, Parkinson’s disease, or congestive heart failure; have a history of myocardial infarction or anginal pain, stroke, liver disease, or renal disease; or are taking medications such as primidone, phenobarbital, carbamazepine, rifampicin, rifabutin, troglitazone, Hypericum perforatum, and valproic acid that may interact with cannabis metabolism.\n\nThe pre-/post-surveys and focus group discussions are an exploratory, qualitative component of this study, and thus a definitive sample size calculation cannot be determined at this stage. We estimate that six focus groups comprising six to eight participants, including two groups of residential care staff, activity staff (care staff who monitor daily activities and social engagement), and family members, will ensure that data saturation has been reached. Written informed consent will be obtained from all participants, including the residential aged-care staff and the next of kin.\n\nRigor\nResidential aged-care staff usually work within the aged-care setting for at least 3 months and therefore are likely to be working in the same facility for the duration of the 4-month trial. The same aged-care staff member will monitor the same participant(s) for the duration of the study and report any changes on the participants’ behalf. To be classified as a residential care staff member, the individual must spend at least two occasions per week with the participant. The same registered nurse will administer the medication for both treatment cycles.\n\nRecruitment\nThe residential aged-care clinical and general managers who have established relationships with the participants and their next of kin will promote the study to those they feel would be eligible to participate. This will be performed through face-to-face conversations.\n\nRandomisation\nThe randomisation process for this study will be done by creating a random number list using a 1:1 ratio allocation to ensure an equal number of cases in both the placebo group (n = 25) and the treatment group (n = 25) using Excel software (Microsoft Corp., Redmond, WA, USA). The determination of participant allocation will be completed by the laboratory manager in the drug manufacturing laboratory, with each case being provided a unique identification (ID) number (1–50). The primary researcher, who is responsible for recruitment, will provide the laboratory manager with the participant’s name to be sequentially matched against with the next available ID number. The laboratory will provide the pharmacy with both CBM and placebo in identical bottles labelled with the ID, but the medical practitioner and research team members will not know the order of treatment until the completion of the study. The pharmacist will place the participant’s name on the bottle before distributing the bottles to the aged-care facilities.\n\nBlinding\nThis is a double-blind study. Therefore, the laboratory manager will be the only individual who will know the group allocation for the participants. This is to ensure that the pharmacist, aged-care staff, medical practitioners, research nurse, family members/next of kin, participants and researchers are all blinded to the participant’s group allocation. Once the study is complete, the laboratory manger will un-blind the information by providing the primary researcher with a list of participants and their group allocation in order to conduct the analysis.\n\nProcedure\nThe study will run for 18 weeks, comprising a 2-week eligibility period for screening and clinical assessment and a 16-week experimental phase encompassing two 6-week cycles of treatment and placebo separated by a 2-week washout period between the treatment cycles and a 2-week washout period following the completion of the second arm (Fig. 1).\nFig. 1 The key phases of the 18-week trial\n\n\n\nEligibility period\nIndividuals who express interest in participating in the study will initially be screened on the basis of inclusion criteria (described above). Following the initial screening process, potential participants will undergo a thorough clinical investigation by a geriatrician to ensure they have the cognitive capacity to provide informed consent using the MMSE. The MMSE [45] is the most widely used cognitive outcome measure to assess the severity of cognitive performance. It comprises 11 items, where a total score out of 30 can be calculated to assess the severity of dementia (25–30 = questionably significant, 20–25 = mild, 10–20 = moderate, 0–10 = severe). Those who seem suitable will be revisited by the geriatrician 1 week after the cognitive tests and will confirm that the participant has understood the purpose of the trial and has recalled the details of the study. Then the primary researcher will invite the eligible participants to enrol in the study and ask them to complete the consent form and provide some demographic and baseline information, including age, sex, education level, weight, medical history including comorbid illnesses, and prescribed medications. The participants will then be randomly allocated to treatment group A or B and receive either CBM oil or placebo for the first 6-week treatment cycle. No adjustments will be made to the participants’ currently prescribed medications.\n\nExperimental phase\nThis phase of the study will take 16 weeks to complete. To minimise the risk of adverse events and variation in the maximum tolerated dose of CBM oil, each participant will receive one dose on the first and second days (2 pm) and two doses (9 am and 2 pm) for the reminder of both treatment cycles. A registered nurse will administer the dose along with a small meal (e.g., morning and afternoon tea), and the rate of titration will be monitored by the pharmacist to ensure it is appropriate for each individual. The participant will gradually receive an increased dose (titration) of the medication over several weeks, as shown in Table 1. During these weeks, the participant along with the care staff will record the presence of, and any change in, any potential adverse events that may be associated with the medication after the first dose, each afternoon when the dose is increased, and again on the final day of medication. If an adverse event is noted, the participant will revert to their previous best tolerated dose using the adverse events and safety protocol listed below.\nTable 1 Titration administration, including dose and number of sprays\n\nDay(s)\tWeek\tDose administered (daily)\tNumber of spray(s) per dose\tAdverse events recorded (time)\t\n9 am\t2 pm\t\n1, 2\t1\t–\t2.5 mg\t1\t3 pm\t\n3, 4\t1\t2.5\t2.5\t1\t\t\n5, 6\t1\t2.5\t5\t1–2\t3 pm\t\n7, 8\t1\t5\t5\t2\t\t\n9, 10\t2\t5\t10\t2–4\t3 pm\t\n11, 12\t2\t10\t10\t4\t\t\n13, 14\t2\t10\t15\t4–6\t3 pm\t\n15, 16\t2/3\t15\t15\t6\t\t\n17, 18\t3\t15\t20\t6–8\t3 pm\t\n19, 20\t3\t20\t20\t8\t\t\n21, 22\t3/4\t20\t25\t8–10\t3 pm\t\n23, 24\t4\t25\t25\t10\t3 pm\t\nAdverse events will be recorded 1 h after drug administration on days of dose increase (days bolded) and on the last day of the treatment period\n\n\n\nAn upper limit of 50 mg/day of THC will be permitted in those who do not experience any adverse events from the medication. Once a participant has reached their maximum tolerated dose (or a total of 50 mg/daily of THC), they will continue to receive that dose until the cessation of the 6-week period. The placebo group will follow a similar titration process using the indicated volumes shown in Table 1. They will continue to receive an increase in the volume of medication until they record an onset of an adverse event, at which time they will continue to take that volume of placebo until the end of the 6-week placebo cycle.\n\nManagement and administration of medication\nThe CBM oil (CogniCann; MGC Pharmaceuticals Ltd., Perth, Australia) will be provided in a sealed 10-ml glass spray bottle which contains a mix of THC and CBD in a 3:2 ratio (25 mg/ml THC; 17 mg/ml CBD) in a medium-chain triglycerides oil base. Each press of the vial will accurately dispense 100 μl of oil that contains 2.5 mg of THC. A total of 50 mg/day of THC and 34 mg/day of CBD can be administered for 4–5 days from one 10-ml glass spray bottle. CogniCann can be stored at room temperature (below 25 °C) for a total of 4 weeks. A certificate of analysis will be provided for each batch upon delivery.\n\nThe placebo will be administered in the same 10-ml glass spray bottle and collected following the procedures describe above. The placebo will comprise a terpene-based oil that contains esters that mimic the smell and taste of CBM.\n\nThe bottles of medication will be provided to the residential aged-care facilities by the affiliated pharmacist. The bottles will be delivered every week and collected again after 7 days of use (even if they are half-full) and returned to the pharmacy, where staff can determine how much was used (or left) and then dispose of the bottles to meet Therapeutic Goods Administration (TGA) requirements. At the start of the titration phase, one bottle will be administered for each participant (because the lower dose of 2.5 mg of THC allows for each bottle to hold 2–3 weeks of the medication). As participants begin to reach a higher dose (titration phase; see Table 1), two bottles will be provided on a weekly basis so that each participant will have sufficient medication to last for 7 days.\n\nData collection\nThe aged-care staff, resident participants with dementia, and nominated next of kin will complete a total of four outcome measures on seven occasions throughout the study. The questionnaires take approximately 20 min to complete and will be completed three times during the first treatment arm (baseline [day 0], after maximum tolerated dose has been reached [day 24], and the end of the treatment cycle [day 42]), three times during the second treatment arm (baseline [day 56], after maximum tolerated dose has been reached [day 80], and the end of the treatment cycle [day 97]) and once following the 2-week washout period after the second treatment arm (day 112). The questionnaires will be administered by the primary researcher.\n\nAdverse events and safety protocol\nAn adverse events protocol will be put into place to minimise any potential harm or risks of receiving additional medication [14]. This will include participants reporting if they have experienced any adverse events 1 h after the increased dose has been administered (see Appendix). If moderate to severe adverse events are recorded (determined as ‘Somewhat worse’ (moderate) or ‘Much worse’ (severe) on the participant’s adverse event record) and these events have not ameliorated by the time for the next dose, the participant will receive the previous best tolerated dose. If the effects of the adverse event(s) have disappeared or become milder and do not interfere with the participant’s daily functioning or well-being, the registered nurse may increase the dose at the indicated rate. Recurrence of adverse events after two attempts to increase the dose will result in the participants remaining at their previous best tolerated dose for the remainder of the intervention period. A participant who experiences an adverse event will stay on the previous dose for another 2 days before the next dose is increased. At the beginning of the titration phase, a staff member at the aged-care facility will be vigilant in monitoring any acute adverse events such as dizziness, discoordination with a danger of falls and injury, and extreme fatigue. Any adverse events recorded will be reported to a facility line manager and will then be communicated to staff during shift changes.\n\nAdditional safety monitoring will be completed by a research nurse who will meet with each participant to discuss their adverse event records and measure their heart rate and blood pressure twice per week. In addition, the participant’s weight and non-invasive body composition measures such as lean body mass, bone mass, body fat percentage, and fat mass will be measured once per week using a portable scale. In addition, a nurse-led review will be completed 2 days into the washout periods to monitor the participant’s withdrawal symptoms once no more medication is being administered.\n\nMeasures\nThe Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) [46] is a questionnaire that measures 12 neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability, aberrant motor behaviour, night-time disturbances and appetite changes). The frequency and severity of each symptom is rated (4-point and 3-point Likert scales). A total score can be calculated by adding the first 10 domains together, and all 12 domain scores can be summed in special circumstances where neurovegetative symptoms are of interest, and a carer disruptiveness score (summing the disruptiveness score of the 10 [or 12] behavioural domains) can be calculated. The NPI-NH can be completed in approximately 10 min.\n\nThe Cohen-Mansfield Agitation Inventory (CMAI) is designed to assess agitation cross three domains, namely physically aggressive behaviour, physically non-aggressive behaviour and verbally agitated behaviour [47]. The CMAI comprises 29 items, uses a 7-point Likert scale (never = (1), less than once per week = (2), once or twice per week = (3), several times per week = (4), once or twice per day = (5), several times per day = (6), several times per hour = (7)), and measures four subscales: aggressive behaviour, physically non-aggressive behaviour, verbally agitated behaviour, and hiding and hoarding. A total score of 203 is calculated, with a higher score indicating a higher frequency in behavioural occurrence, and the measure takes approximately 5 min to complete.\n\nThe Quality of Life in Alzheimer’s Disease (QOL-AD) instrument is designed to measure aspects important for an individual’s QOL. The QOL-AD consists of 13 items using a 4-point Likert scale (poor = (1), fair = (2), good = (3), and excellent = (4)) and is designed for both self-report and proxy report [48]. The QOL-AD measures four domains (physical health, mental health, social, and function) and can be completed with people with a wide range of dementia severity [49]. A total score out of 52 is calculated, with a higher score indicating a higher QOL. The self-report version can be completed in about 10–15 min and the proxy report in about 5 min. A composite score can also be calculated (participant QOL-AD × 2 + carer QOL-AD × 3).\n\nThe Abbey Pain Scale comprises six items assessing vocalisation; facial expression; change in body language; and behavioural, physiological and physical changes [50]. This questionnaire uses a 4-point Likert scale (absent = 0, mild = (1), moderate = (2), severe = (3)), and a total score out of 18 is calculated. The severity of pain is indicated as mild (score of 3–7), moderate (8–13) and severe (14+) and can be completed in less than 5 min.\n\nProcess evaluation outcomes\nThe one-page pre- and post-surveys will be administered to aged-care staff and next of kin at the beginning of the first treatment cycle and at the end of the second treatment cycle. These surveys comprise seven to nine questions regarding individuals’ perceptions towards CBM oil use and the symptoms of dementia they find most challenging. A total of six questions will be asked during the focus group discussions. These questions relate to positive and negative observations among those taking CBM oil, as well as changes in perceptions, knowledge and benefits regarding the use of CBM use.\n\nData analysis\nQuantitative\nThe results of questionnaires completed on behalf of the aged-care staff, participants and family members will be analysed using IBM SPSS Statistics version 25 software (IBM, Armonk, NY, USA). The responses from the aged-care staff will be the main responses considered for analysis. Where available, participants and family responses will be included for secondary analysis. To examine group differences, the participants will be categorised according to their treatment cycle group allocation (group A or group B). Descriptive statistics will be derived. Each variable will be tested for normality. For those variables that meet the normality assumption, two-sided paired and/or independent t tests will be used to examine group differences within and between groups. If the normality assumption is violated, then non-parametric tests such as the Wilcoxon signed-rank test will be used. Within-subject differences of the four measurements between the first and second washout periods will be tested using paired t tests to ensure that the washout phase is long enough to rule out any carryover effects [51, 52]. All data collection points will be examined using general linear mixed modelling techniques to see if any changes in behaviour, QOL or pain have occurred over the duration of both treatment cycles. The covariates of weight, average dose of medication, and baseline measures will be controlled for in each model, and any interactions will be tested and reported. The proportion of adverse events during the CBM and placebo phases will be tested and reported for each individual. NPI-NH is the primary outcome measure for this study. All other measures (CMAI, QOL-AD, and Abbey Pain Scale) have been included for secondary analysis. The CMAI will be analysed using the reliability change methodology compared with the NPI-NH to allow small changes to be reported [53]. The α-value will be set at 0.05. In the instance where a participant withdraws halfway through a treatment cycle, the information collected prior to withdrawal will be retained in the study because their personal information will have been de-identified. The data management of the information collected will follow standard university procedures, be stored in a locked cabinet for a period of 15 years, be stored on a password-protected computer, and be backed up regularly in a secure format.\n\nQualitative\nNVivo 12 software (QSR International, Doncaster, Australia) will be used for qualitative data management and assistance in the analysis of both the pre- and post-surveys and in the focus groups. Qualitative content analysis will be used to analyse the surveys to assess similarities and differences between responses. The focus group results will be transcribed verbatim, and the transcripts will be thematically analysed by repeated readings and a subsequent open coding process followed by line-by-line coding to identify key themes. To avoid bias, a triangulated approach including reflectivity by the primary researcher during the interview process, member checking to establish confirmability, and verbatim quotes to establish credibility will be used. The primary researcher and the research team at the University of Notre Dame Australia will have access only to the final data set. The data will be stored in university computers on a locked storage drive.\n\nDiscussion\nTo our knowledge, this is one of the first trials within Australia to evaluate the use of a purified CBM oil at the individual level among those with dementia to examine behavioural effects, QOL, and pain and discomfort. Only a handful of crossover trials have been conducted [14, 16, 41, 42, 54], although the majority have used fixed doses and have not incorporated an individually tailored dosing regimen. Soto et al. [28] reviewed 18 randomised clinical trials examining drugs prescribed for agitation and aggression and found large variations not only in the chosen questionnaires to measure these symptoms but also in the inclusion criteria. On the basis of their results, Soto et al. [28] suggested that trials lasting 9–12 weeks were adequate for assessing an acute response, whereas longer trials (6–12 months) were effective for assessing the stability of a response. The 18-week duration of this study is appropriate to assess the initial dose response [28], and the trial design is also reflective of other protocols of crossover studies and includes two 2-week washout periods to ensure patient safety and a chance for the medication to metabolise out of the body. For example, Babalonis et al. [31] designed a protocol to examine the use of a THC:CBD oromucosal spray among post-stroke spasticity patients and included two 4-week treatment cycles with a 2-week washout period between both cycles.\n\nThere are a number of strengths of our study. First, all participants will have a medical diagnosis of dementia. This ensures that the diagnosis is in line with the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [55]. Second, the residential aged-care staff spend a large amount of time with the participants, so they will be able to observe small changes, leading to accuracy in recording of the results. When possible, these results will also be compared with information from the participants and their next of kin to examine similarities and differences. Beattie et al. [56] published a protocol paper outlining a national project to collect multiple QOL perspectives from the care staff, family members and those living with dementia. Comparisons between care staff, family members and self-report QOL scores showed a linear relationship between reporters, with the residents often rating their QOL higher than the care staff [57, 58].\n\nAs an additional precautionary step, two separate questionnaires assessing behavioural symptoms have been included to ensure that the smallest effects of CBM oil are observed. A strict safety protocol monitoring of adverse events and nurse-led reviews during the washout periods will also be followed to ensure participant safety, which has been included due to the average age of the participants, additional medications currently prescribed, and the likelihood of having a comorbid condition. Weier and Hall [15] suggested that the therapeutic benefits of CBM are observed among patients with dementia when administered alongside adjacent therapy or medication. In addition, the dose of medication will be titrated to ensure that each participant receives their best tolerated dose and minimises the onset of any adverse events. This process of ‘start low and go slow’ is reflective of other studies as well as government documentation from Queensland Health [59, 60]. Educational training with the aged-care staff will be completed before the first participant is recruited to prevent unexpected issues arising during the trial and to ensure that they are familiar with the structure of the overall research protocol as well as the questionnaires.\n\nThis study has used a holistic approach to gain more in-depth information about BPSD and to capture staff and family members’ perceptions of CBM. The inclusion of the qualitative phase is important because little research has been completed to gain understanding of personal views of CBM use and the effects thereof in this setting. This approach allows the researchers to understand the perceived strengths and challenges in the use of cannabis within an institutional setting. Many symptoms associated with dementia, such as wandering, agitation, aggression, and psychotic behaviours, contribute to fatigue and burnout experienced by many caregivers [61]. Feast et al. [62] reviewed the relationship of BPSD and well-being of informal caregivers (child-adult or spousal caregivers) and found that the most distressing symptoms for caregivers were depressive behaviours, agitation and aggression, apathy (including irritability), aberrant motor behaviours, and delusions.\n\nA number of challenges have been identified in the proposed study. It may be difficult to find those with a dementia diagnosis who have the cognitive capacity to give informed consent, because many experience a loss of short-term memory, intellectual reasoning, rationality, and social skills [1, 2]. This may lead to difficulty in recruiting participants into the trial and excluding those who do not have the capacity to give informed consent; yet, they are potentially the ones who exhibit a greater number of behavioural occurrences. Those who experience mild to moderate dementia still exhibit symptoms such as depression and anxiety and both verbal and physical agitation [2]. However, due to the limited legislation regarding including those who do not have the cognitive capacity to give informed consent in research projects, this limits who can be included in this study. The replication of this study design to include those with a moderate to severe diagnosis would warrant further generalisability of the results. Irreversible progression of cognitive impairment, the associated complications and comorbidities, and frailty of the participants may lead to participants dropping out of the study. To accommodate this, we have included a 20% increase in the sample size. It is also difficult to know if the questionnaires chosen for this study are suitable and sensitive enough to measure the changes attributed to the use of CBM oil, because no ‘gold standard’ exists to measure BPSD. Therefore, both the NPI-NH and the CMAI have been selected to account for the small effects. The pharmacodynamics of the medication will be monitored during the treatment cycles through the use of non-invasive body composition measures and monitoring of heart rate, blood pressure and weight. These measures will be collected by a research nurse external to the aged-care facilities to improve the feasibility of the study, to avoid additional workloads placed on the aged-care staff, and to ensure that each participant is receiving their best tolerated dose. In addition, only one residential staff member has been selected to complete the questionnaires, because they spend a great deal of time with the residents and can report symptoms easily. Independent reviews have not been selected for this study, because they are unfamiliar to the participants, which may lead to inaccuracy in recording of the results.\n\nTrial status\nThe trial has been registered with the Australian New Zealand Clinical Trials Registry. The registration number is ACTRN12619000474156, and the trial was registered on 21 March 2019. Recruitment is set to begin in Feburary 2020. The approximate date that the recruitment will be completed is 20 July 2020.\n\nSupplementary information\n\nAdditional file 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist.\n\n \n\n\nAppendix\nAdverse events associated with THC and CBD\nAdverse events will most likely occur within 1 h of administration of the medication but will often resolve within 48 h of treatment. Participants will report their adverse events to make sure the titration is appropriate for them.\n\nCompared with how you normally feel, have you experienced a change in any of the symptoms described below in the last hour? Tick the most appropriate box below.\n\tNo\tYes (tick box below)\t\nBetter\tSomewhat better\tSame as usual\tSomewhat worse\tMuch worse\t\nDrowsiness/fatigue\t\t\t\t\t\t\t\nDizziness\t\t\t\t\t\t\t\nDry mouth\t\t\t\t\t\t\t\nSore throat\t\t\t\t\t\t\t\nAnxiety\t\t\t\t\t\t\t\nNausea\t\t\t\t\t\t\t\nMemory decline or attention deficits\t\t\t\t\t\t\t\nJoy or euphoria\t\t\t\t\t\t\t\nBlurred vision\t\t\t\t\t\t\t\nHeadache\t\t\t\t\t\t\t\nParanoia\t\t\t\t\t\t\t\nDepression\t\t\t\t\t\t\t\nLack of coordination\t\t\t\t\t\t\t\nDiarrhoea\t\t\t\t\t\t\t\nAppetite\t\t\t\t\t\t\t\nSleep disturbance\t\t\t\t\t\t\t\nTo be completed during the titration phase and following the last dose in each treatment arm\n\n\n\nAbbreviations\nBPSDBehavioural and neuropsychiatric symptoms of dementia\n\nCBDCannabidiol\n\nCBMCannabinoid-based medicine\n\nCMAICohen-Mansfield Agitation Inventory\n\nMMSEMini Mental State Examination\n\nNPI-NHNeuropsychiatric Inventory Questionnaire–Nursing Homes\n\nQOLQuality of life\n\nQOL-ADQuality of Life in Alzheimer’s disease\n\nTGATherapeutic Goods Administration\n\nTHCDelta-9-tetrahydrocannabinol\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s13063-020-4085-x.\n\nAcknowledgements\nThis research is financially support by MGC Pharmaceuticals Ltd., an Australian registered company with global connections that specialises in the manufacture of CBM in its good manufacturing practice (GMP)-certified laboratory.\n\nAuthors’ contributions\nAT, CB, MB and JC designed the trial protocol alongside MGC Pharmaceuticals Ltd. AT drafted the manuscript, and CB, MC, AV, JS and JC contributed to the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis project has been fully funded by MGC Pharmaceuticals. MGC Pharmaceuticals informed the design of the study. They will not be involved in the data collection or in the analysis or interpretation of the data. Meetings held between UNDA and MGC Pharmaceuticals during the collection and analysis of data will only be outlined in a general sense. No specific information about the results will be shared.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nEthics approval has been granted by the Human Research Ethics Committee at the University of Notre Dame Australia (UNDA; approval number 018091F). All participants, including the residents and their family members, will need to consent to participate. The results gathered beyond this protocol paper will be presented for the total sample, not for individual cases, and all participants will be given a unique identification number to de-identify their information.\n\nCompeting interests\nThe authors declare that there may be a perceived conflict of interest in undertaking research funded by MGC Pharmaceuticals, the manufacturer of the drug used in the trial; a number of precautionary steps have been implemented to minimise these. These steps include input on study design and drug doses obtained in the development of the research protocol and securing TGA approval for provision of the drug. All MGC Pharmaceuticals staff will be excluded from the trial itself, including the data collection as well as analysis and interpretation of the data. In joint management meetings, the progress of the study will only be discussed in broad terms to ensure compliance with budgetary issues and appropriate responses to any serious adverse events. UNDA has written permission from MGC Pharmaceuticals Ltd. for a worldwide, non-exclusive, royalty-free license to use the project intellectual property for non-commercial research purposes, including consent to publish research findings regardless of the results. The results will be disseminated via brief reports provided to the participating aged care facilities, as well as through manuscript publications and conference presentations.\n==== Refs\nReferences\n1. Alzheimer’s Disease International. The global voice on dementia 2017. https://www.alz.co.uk/. Accessed 5 Jan 2018.\n2. Anand A Khurana P Chawla J Sharma N Khurana N Emerging treatments for the behavioral and psychological symptoms of dementia CNS Spectr 2018 23 6 361 369 10.1017/S1092852917000530 28911339 \n3. Kales HC Gitlin LN Lyketsos CG Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. 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Feast A Moniz-Cook E Stoner C Charlesworth G Orrell M A systematic review of the relationship between behavioral and psychological symptoms (BPSD) and caregiver well-being Int Psychogeriatr 2016 28 11 1761 1774 10.1017/S1041610216000922 27345942\n\n", "fulltext_license": "CC BY", "issn_linking": "1745-6215", "issue": "21(1)", "journal": "Trials", "keywords": "Behavioural and neuropsychiatric symptoms of dementia (BPSD); Crossover trial; Dementia; Medicinal cannabis; Pain; Quality of life", "medline_ta": "Trials", "mesh_terms": "D000368:Aged; D002186:Cannabinoids; D018592:Cross-Over Studies; D003704:Dementia; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D064086:Medical Marijuana; D000073216:Mental Status and Dementia Tests; D009735:Nursing Homes; D010146:Pain; D010147:Pain Measurement; D010938:Plant Oils; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome", "nlm_unique_id": "101263253", "other_id": null, "pages": "188", "pmc": null, "pmid": "32059690", "pubdate": "2020-02-14", "publication_types": "D000078325:Clinical Trial Protocol; D016428:Journal Article", "references": "25230245;28923526;27624148;25678176;14966439;26482028;19370677;27561138;27267317;1202204;24634659;28088032;27665036;28911339;28861514;28833749;21364345;12021425;25752889;15258006;28940504;16521031;31559336;17140265;30383388;28300462;25972490;16239180;14583744;27345942;16230747;25899853;9309469;28457054;24635665;28631194;25821504;25024327;27548592;28636769;27713372;21954480;26046666;9153155;26757043;28112021;16022061;23975378;25226218;22305029;25801347;22567063;18081000;25237116;23597932", "title": "Use of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial.", "title_normalized": "use of cannabinoid based medicine among older residential care recipients diagnosed with dementia study protocol for a double blind randomised crossover trial" }	[ { "companynumb": "US-OTSUKA-2020_010254", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Timler A, Bulsara C, Bulsara M, Vickery A, Smith J, Codde J. Use of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial. Trials. 2020;21(1):NIL_0081-91", "literaturereference_normalized": "use of cannabinoid based medicine among older residential care recipients diagnosed with dementia study protocol for a double blind randomised crossover trial", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19916557, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "Renal tubular acidosis (RTA) is a rare complication of renal involvement of systemic lupus erythematosus (SLE). We describe a 24-year-old male with type IV lupus nephropathy as a presenting manifestation of SLE. He presented with improvement of renal function following induction therapy with three pulses of methylprednisolone and 500 mg biweekly pulses of cyclophosphamide. However, a week after the first pulse of cyclophosphamide, the patient presented with a significant increase in legs edema and severe hyperkalemia. Type IV RTA associated with hyporeninemic hypoaldosteronism was suspected in the presence of metabolic acidosis with a normal anion gap, severe hyperkalemia without worsening renal function, and urinary pH of 5. RTA was confirmed with a transtubular potassium concentration gradient of 2 and low levels of plasma aldosterone, renin, angiotensin II, and cortisol. Intravenous bicarbonate, high-dose furosemide, and fludrocortisone were administered with normalization of potassium levels and renal function.", "affiliations": "Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain [email protected].", "authors": "Sánchez-Marcos\|C\|C\|;Hoffman\|V\|V\|;Prieto-González\|S\|S\|;Hernández-Rodríguez\|J\|J\|;Espinosa\|G\|G\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D001639:Bicarbonates; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D049994:Sodium Potassium Chloride Symporter Inhibitors", "country": "England", "delete": false, "doi": "10.1177/0961203315603143", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "25(3)", "journal": "Lupus", "keywords": "Lupus nephritis; hyperkalemia; renal tubular acidosis", "medline_ta": "Lupus", "mesh_terms": "D000138:Acidosis; D000893:Anti-Inflammatory Agents; D001639:Bicarbonates; D004359:Drug Therapy, Combination; D004487:Edema; D005938:Glucocorticoids; D006801:Humans; D006947:Hyperkalemia; D006994:Hypoaldosteronism; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D020551:Pulse Therapy, Drug; D049994:Sodium Potassium Chloride Symporter Inhibitors; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "9204265", "other_id": null, "pages": "307-9", "pmc": null, "pmid": "26345674", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Renal tubular acidosis type IV as a complication of lupus nephritis.", "title_normalized": "renal tubular acidosis type iv as a complication of lupus nephritis" }	[ { "companynumb": "ES-MYLANLABS-2016M1014296", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075480", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal tubular acidosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Unmasking of previously unidentified disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SANCHEZ-MARCOS C, HOFFMAN V, PRIETO-GONZALEZ S, HERNANDEZ-RODRIGUEZ J, ESPINOSA G. RENAL TUBULAR ACIDOSIS TYPE IV AS A COMPLICATION OF LUPUS NEPHRITIS. LUPUS 2016;25(3):307-309.", "literaturereference_normalized": "renal tubular acidosis type iv as a complication of lupus nephritis", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20160408", "receivedate": "20160408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12249128, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]
{ "abstract": "The authors examined whether lamotrigine is a clinically effective and cost-effective treatment for people with borderline personality disorder.\n\n\n\nThis was a multicenter, double-blind, placebo-controlled randomized trial. Between July 2013 and November 2016, the authors recruited 276 people age 18 or over who met diagnostic criteria for borderline personality disorder. Individuals with coexisting bipolar affective disorder or psychosis, those already taking a mood stabilizer, and women at risk of pregnancy were excluded. A web-based randomization service was used to allocate participants randomly in a 1:1 ratio to receive either an inert placebo or up to 400 mg/day of lamotrigine. The primary outcome measure was score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. Secondary outcome measures included depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, and adverse events.\n\n\n\nA total of 195 (70.6%) participants were followed up at 52 weeks, at which point 49 (36%) of those in the lamotrigine group and 58 (42%) of those in the placebo group were taking study medication. The mean ZAN-BPD score was 11.3 (SD=6.6) among those in the lamotrigine group and 11.5 (SD=7.7) among those in the placebo group (adjusted difference in means=0.1, 95% CI=-1.8, 2.0). There was no evidence of any differences in secondary outcomes. Costs of direct care were similar in the two groups.\n\n\n\nThe results suggest that treating people with borderline personality disorder with lamotrigine is not a clinically effective or cost-effective use of resources.", "affiliations": "From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.", "authors": "Crawford\|Mike J\|MJ\|;Sanatinia\|Rahil\|R\|;Barrett\|Barbara\|B\|;Cunningham\|Gillian\|G\|;Dale\|Oliver\|O\|;Ganguli\|Poushali\|P\|;Lawrence-Smith\|Geoff\|G\|;Leeson\|Verity\|V\|;Lemonsky\|Fenella\|F\|;Lykomitrou\|Georgia\|G\|;Montgomery\|Alan A\|AA\|;Morriss\|Richard\|R\|;Munjiza\|Jasna\|J\|;Paton\|Carol\|C\|;Skorodzien\|Iwona\|I\|;Singh\|Vineet\|V\|;Tan\|Wei\|W\|;Tyrer\|Peter\|P\|;Reilly\|Joseph G\|JG\|;\|\|\|", "chemical_list": "D014150:Antipsychotic Agents; D000077213:Lamotrigine", "country": "United States", "delete": false, "doi": "10.1176/appi.ajp.2018.17091006", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-953X", "issue": "175(8)", "journal": "The American journal of psychiatry", "keywords": "Borderline Personality Disorder; Lamotrigine; Mood Stabilizer; Randomized Controlled Trial", "medline_ta": "Am J Psychiatry", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001883:Borderline Personality Disorder; D003362:Cost-Benefit Analysis; D004311:Double-Blind Method; D005260:Female; D017048:Health Care Costs; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D055118:Medication Adherence; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome", "nlm_unique_id": "0370512", "other_id": null, "pages": "756-764", "pmc": null, "pmid": "29621901", "pubdate": "2018-08-01", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial.", "title_normalized": "the clinical effectiveness and cost effectiveness of lamotrigine in borderline personality disorder a randomized placebo controlled trial" }	[ { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-02573", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200694", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BORDERLINE PERSONALITY DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CRAWFORD MJ, SANATINIA R, BARRETT B, CUNNINGHAM G, ET AL.. THE CLINICAL EFFECTIVENESS AND COST?EFFECTIVENESS OF LAMOTRIGINE IN BORDERLINE PERSONALITY DISORDER: A RANDOMIZED PLACEBO?CONTROLLED TRIAL. AM J PSYCHIATRY.. 2018?175(8):756?764", "literaturereference_normalized": "the clinical effectiveness and cost effectiveness of lamotrigine in borderline personality disorder a randomized placebo controlled trial", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180810", "receivedate": "20180810", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15263668, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-02571", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200694", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BORDERLINE PERSONALITY DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CRAWFORD MJ, SANATINIA R, BARRETT B, CUNNINGHAM G, ET AL.. THE CLINICAL EFFECTIVENESS AND COST?EFFECTIVENESS OF LAMOTRIGINE IN BORDERLINE PERSONALITY DISORDER: A RANDOMIZED PLACEBO?CONTROLLED TRIAL. AM J PSYCHIATRY.. 2018?175(8):756?764", "literaturereference_normalized": "the clinical effectiveness and cost effectiveness of lamotrigine in borderline personality disorder a randomized placebo controlled trial", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180810", "receivedate": "20180810", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15263666, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-02572", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200694", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BORDERLINE PERSONALITY DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CRAWFORD MJ, SANATINIA R, BARRETT B, CUNNINGHAM G, ET AL.. THE CLINICAL EFFECTIVENESS AND COST?EFFECTIVENESS OF LAMOTRIGINE IN BORDERLINE PERSONALITY DISORDER: A RANDOMIZED PLACEBO?CONTROLLED TRIAL. AM J PSYCHIATRY.. 2018?175(8):756?764", "literaturereference_normalized": "the clinical effectiveness and cost effectiveness of lamotrigine in borderline personality disorder a randomized placebo controlled trial", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180810", "receivedate": "20180810", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15263646, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]
{ "abstract": "Omeprazole significantly increases duodenal prostaglandin E2 synthesis. Prostaglandins are involved in hair growth regulation: prostaglandin E2 and prostaglandin F2 alpha stimulate hair growth, and prostaglandin D2 has an inhibitory effect. The use of omeprazole can cause acquired generalized hypertrichosis by increasing prostaglandin E2 levels.", "affiliations": "Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Dermatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Pediatrics, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.", "authors": "Elosua-González\|Marta\|M\|http://orcid.org/0000-0002-4227-9316;Campos-Domínguez\|Minia\|M\|http://orcid.org/0000-0002-4638-2265;Bancalari\|Daniel\|D\|;Noguera-Morel\|Lucero\|L\|;Hernández-Martín\|Angela\|A\|;Huerta-Aragonés\|Jorge\|J\|;Torrelo\|Antonio\|A\|http://orcid.org/0000-0002-5940-6916", "chemical_list": "D054328:Proton Pump Inhibitors; D009853:Omeprazole", "country": "United States", "delete": false, "doi": "10.1111/pde.13496", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "35(4)", "journal": "Pediatric dermatology", "keywords": "drug reaction; hair disorders", "medline_ta": "Pediatr Dermatol", "mesh_terms": "D002648:Child; D006801:Humans; D006983:Hypertrichosis; D007223:Infant; D008297:Male; D009853:Omeprazole; D054328:Proton Pump Inhibitors", "nlm_unique_id": "8406799", "other_id": null, "pages": "e212-e214", "pmc": null, "pmid": "29582462", "pubdate": "2018-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Omeprazole-induced hypertrichosis in two children.", "title_normalized": "omeprazole induced hypertrichosis in two children" }	[ { "companynumb": "ES-IMPAX LABORATORIES, INC-2018-IPXL-01278", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CROMOLYN SODIUM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, EVERY 8HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "URTICARIA PIGMENTOSA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CROMOGLYCATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CETIRIZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "URTICARIA PIGMENTOSA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CETIRIZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "075785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE CAPSULE", "drugdosagetext": "40 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE DELAYED RELEASE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "075785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE CAPSULE", "drugdosagetext": "20 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ABDOMINAL PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE DELAYED RELEASE" } ], "patientagegroup": null, "patientonsetage": "8", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intussusception", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertrichosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ELOSUA-GONZ?LEZ M, CAMPOS-DOM?NGUEZ M, BANCALARI D, NOGUERA-MOREL L,HERN?NDEZ-MART?N A, HUERTA-ARAGON?S J ET AL.. OMEPRAZOLE-INDUCED HYPERTRICHOSIS IN TWO CHILDREN. PEDIATR DERMATOL. 2018?00:1-3", "literaturereference_normalized": "omeprazole induced hypertrichosis in two children", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20180423", "receivedate": "20180423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14790627, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "Baclofen is used in the treatment of muscle spasms by acting as an agonist GABAB receptors. Limited case reports describing baclofen withdrawal-induced delirium have largely been demonstrated to occur upon cessation of intrathecal baclofen administration. Fewer reports have characterized the presentation from oral baclofen withdrawal. We describe a case of a patient, MM, who presented with hyperactive delirium with various, associated, behavioral, perceptual, cognitive, and movement disturbances following abrupt withdrawal of oral baclofen. Symptomatic management of occurring during the withdrawal state with antipsychotics and benzodiazepines has been reported previously. Similarly, MM's perceptual and behavioral disturbances were managed with antipsychotics during her admission. However, addressing the underlying cause by reinstating and slowly tapering off baclofen has also been demonstrated to be an effective, targeted approach.", "affiliations": "Psychiatry, University of Kentucky, Bowling Green, USA.;Psychiatry, University of Kentucky, Bowling Green, USA.", "authors": "Sanders\|Benjamin J\|BJ\|;Ali\|Ziad\|Z\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.14979", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14979\nPsychiatry\nOral Baclofen Withdrawal Resulting in Hyperactive Delirium: A Case Report\nMuacevic Alexander\nAdler John R\nSanders Benjamin J 1\nAli Ziad 1\n1 Psychiatry, University of Kentucky, Bowling Green, USA\nBenjamin J. Sanders [email protected]\n12 5 2021\n5 2021\n13 5 e1497912 5 2021\nCopyright © 2021, Sanders et al.\n2021\nSanders et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/59197-oral-baclofen-withdrawal-resulting-in-hyperactive-delirium-a-case-report\nBaclofen is used in the treatment of muscle spasms by acting as an agonist GABAB receptors. Limited case reports describing baclofen withdrawal-induced delirium have largely been demonstrated to occur upon cessation of intrathecal baclofen administration. Fewer reports have characterized the presentation from oral baclofen withdrawal. We describe a case of a patient, MM, who presented with hyperactive delirium with various, associated, behavioral, perceptual, cognitive, and movement disturbances following abrupt withdrawal of oral baclofen. Symptomatic management of occurring during the withdrawal state with antipsychotics and benzodiazepines has been reported previously. Similarly, MM’s perceptual and behavioral disturbances were managed with antipsychotics during her admission. However, addressing the underlying cause by reinstating and slowly tapering off baclofen has also been demonstrated to be an effective, targeted approach.\n\noral\nbaclofen\ndelirium\npsychosis\nwithdrawal\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nBaclofen is a synthetic chlorophenyl-butanoic acid derivative that is utilized for treatment of muscle spasms by acting as an agonist on GABAB receptors [1]. Abrupt withdrawal of baclofen has been found to demonstrate a range of adverse reactions including behavioral, perceptual, emotional, and movement disturbances [2-5]. We present a case demonstrating the evolving presentation of oral baclofen withdrawal to improve early recognition and expedition of appropriate management.\n\nCase presentation\n\nMM is a 58-year-old female who presented to the emergency department (ED) on four separate occasions, all days apart from each other, with complaints of twitching in her upper and lower extremities, lower extremity weakness, and falls that had become increasingly worse over the past four days.\n\nMM had a past psychiatric history significant for depression and past medical history significant for fibromyalgia and chronic back pain, which was managed with trazodone 100 mg nightly, baclofen 10 mg three times daily, as needed, oxycodone 10 mg every 8 hours, as needed, and zolpidem 10 mg nightly.\n\nDuring her initial evaluation in the emergency room, MM demonstrated significant difficulty with concentration, tangential and disorganized thinking with occasional non-goal directed responses, impaired reasoning, “strange affect,” “bizarre behaviors,” with one provider reporting she was “talking out of her head.” Upon evaluation, a basic metabolic panel (BMP) found to be significant for an acute kidney injury with a blood urea nitrogen (BUN) of 36 and creatinine of 1.09 and mildly tachycardic and tachypneic. All other initial laboratory results, including complete blood count (CBC) and urinalysis, were found to be unremarkable. Urine drug screen was positive for oxycodone, to which she was prescribed. While in the ED, psychiatry was consulted for evaluation for disposition.\n\nUpon evaluation, MM endorsed significant paranoia towards the nursing staff in the ED. She also demonstrated tangential thought processes with flight-of-ideas. She reported experiencing auditory hallucinations in the form of laughter and was observed responding to internal stimuli. She was found to have intact short- and long-term memory; however, she was alert and oriented only to self and location. She is also observed to have bilateral lower extremity weakness and abnormal upper extremity movements. She reported her mood as depressed, but demonstrated an expansive and incongruent affect.\n\nCollateral information was obtained from MM’s son, who stated that he had also first noticed MM’s twitching roughly four days prior to her first ED visit. He also reported that around that same time, she had been intermittently appearing disoriented, demonstrating disorganized speech, and believed that MM had been experiencing auditory hallucinations. He reported that at her baseline, MM was coherent and oriented, and has never been observed responding to internal stimuli in the past.\n\nAt that time, it was recommended that MM be admitted to the hospital and worked up for medical/neurological causes for delirium. Initially, she was not continued on any of her home medications. On her first night after admission, MM required one PRN of 5 mg oral olanzapine and another 10 mg PRN of intramuscular ziprasidone for agitation. A head CT was ordered for acute mental status change and found only to demonstrate chronic small vessel disease. An EEG was also ordered and demonstrated mild to moderate diffuse encephalopathy. A urine culture found to be positive for E. coli; however, as she was asymptomatic, the primary medical team did not treat her asymptomatic bacturia.\n\nOn day 2 of MM’s hospital stay, she was observed to be alert and oriented to self and location with fluctuating orientation to location. MM continued to demonstrate involuntary twitches in the upper and lower extremities. At times, her speech was incoherent and disorganized. She was also occasionally observed responding to internal stimuli. Her affect was described as bizarre with inappropriate affect and incongruent to the stated mood of being “tired.” It was at this time, additional collateral was able to be obtained from MM’s daughter, who stated that MM had been taking up to triple her prescription of baclofen. Based on the information obtained from her daughter, as well as the previous information from her son and pharmacy records, it was believed that MM had run out of her baclofen about four days prior to her first presentation to the ED. This coincided with the first onset of her symptoms. It was also believed by some members of her care team that MM may have taken all of her prescribed baclofen and had recently run out in the days leading up to her presentation in the ED. For symptomatic management, psychiatry started MM on risperidone 1 mg twice daily for hallucinations and overnight agitation. Based on the information received from collateral, MM continued to be observed for delirium. However, as the treating teams were unsure whether MM’s presentation was due to baclofen overdose or withdrawal, MM continued to only receive symptomatic management early on during her stay.\n\nOver the next two days, MM intermittently continued to be observed responding to internal stimuli and demonstrating bizarre behaviors, thought blocking, intermittent poverty of thought, impaired concentration, and fluctuating orientation. While the involuntary twitching in her extremities continued to decrease in frequency and intensity. Throughout her stay, MM continued to receive intravenous fluids. While her BUN and creatinine peaked on the third day of her admission at 56 and 2.84, respectively, with continued fluids her BUN and creatinine trended downwards with her last BUN and creatinine recorded at 34 and 1.17, respectively.\n\nOn day 6, MM was found to be much more calm and cooperative when seen by the psychiatry team on rounds. She was alert and oriented x3. Her thought processes were much more linear, goal-directed, and coherent. No bizarre behaviors or gestures were observed. While interviewing MM, she did report that she had been over-using her baclofen, but was unable to recall precisely how many pills she was taking daily. After discussion with the treating teams, based on MM’s presentation it was believed that delirium was primarily due to baclofen withdrawal that may have been exacerbated by an acute kidney injury. Psychiatry discussed the potential for future baclofen-induced delirium, especially if not taken as prescribed, with MM. She was discharged home with a plan to follow up with psychiatry and neurology on an outpatient basis.\n\nDiscussion\n\nThe presentation of MM’s symptoms is consistent with previous case reports of baclofen withdrawal. The majority of published case reports of baclofen withdrawal delirium have occurred in the context of intrathecal baclofen administration; fewer case reports have been published examining the presentation of oral baclofen withdrawal delirium [2-6]. MM demonstrated musculoskeletal findings, such as abnormal, involuntary movements in her extremities throughout much of the early course of her hospitalization. Similar, intermittent, involuntary movements, and bilateral pupil dilation have also been described in various case reports regarding individuals presenting with baclofen withdrawal [2-6]. Similar to other accounts, MM demonstrated tachycardia when she presented to the ED; however, MM did not have similar characteristic vital signs, such as hypertension or hyperthermia that have also been reported [5].\n\nAmong MM’s most noteworthy and characteristic symptoms of baclofen withdrawal were her psychiatric symptoms. MM demonstrated significant impairments in her thought processes, which were noted to be tangential, disorganized, non-linear, and with flight of ideas, with one ED physician stating she was “talking out of her head.” Several case reports similarly describe patients in acute baclofen withdrawal who also demonstrated formal thought disorders, with one case report by Arnold et al. (1980) also describing the presentation of a patient in baclofen withdrawal who they described as “talking out of his head” [2-4]. Additionally, MM demonstrated impaired concentration, fluctuating orientation, perceptual disturbances in the form of auditory and visual hallucinations, paranoia, and sleep disturbances consistent with delirium due to baclofen withdrawal.\n\nDue to questions about whether MM’s delirium was due to baclofen withdrawal versus intoxication, MM only received symptomatic management for her perceptual and behavioral disturbances throughout her stay. If this had been identified earlier, MM may have, instead, been restarted on a low-dose baclofen taper, which has been previously documented and recommended as a therapeutic approach [2-6]. In a review of 23 case reports of baclofen withdrawal, Leo and Baer (2005) found that 10 cases (43.5%) were managed by reinstituting baclofen alone, whereas reinstitution of baclofen with another agent, such as an antipsychotic, a benzodiazepine, or an anticonvulsant, were reported in 4 (17.4%), 6 (26.1%), and 1 (4.3%) case(s), respectively [4].\n\nThe presentation of baclofen withdrawal consists of a cluster of signs and symptoms, including perceptual disturbances, sleep disturbance, impaired thought processes, expansive affect, abnormal movements, disorganized speech, impaired attention, and disorientation, which may be variably present. In a patient presenting with these symptoms, it is imperative to rule out medical and pharmacological causes, especially in a patient with no history significant for psychosis or mania. While the majority of published case reports have described patients presenting in delirium from withdrawal from intrathecal baclofen, delirium from oral baclofen withdrawal can also be observed, as was the case with MM. Prompt identification of the etiology of this presentation will help guide subsequent management considerations by providers.\n\nConclusions\n\nLike withdrawal from intrathecal baclofen, withdrawal from oral baclofen can present with various cognitive, behavioral, perceptual, and motor disturbances. While symptomatic management of withdrawal symptoms with antipsychotics and benzodiazepines has been demonstrated, reinstituting and slowly tapering off baclofen has been demonstrated to be more targeted approach and effective approach.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 PubChem Compound Summary for CID 2284, Baclofen 52021 13 2021 2284 2021 https://pubchem.ncbi.nlm.nih.gov/compound/Baclofen\n2 Dyskinesia and psychosis in a patient following baclofen withdrawal Am J Psychiatry Kirubakaran V Mayfield D Rengachary S 692 693 141 1984 6711693\n3 Manic psychosis following rapid withdrawal from baclofen Am J Psychiatry Arnold ES Rudd SM Kirshner H 1466 1467 137 1980 7435695\n4 Delirium associated with baclofen withdrawal: a review of common presentations and management strategies Psychosomatics Leo RJ Baer D 503 507 46 2005 16288128\n5 Intrathecal baclofen overdose and withdrawal Pediatr Emerg Care Shirley KW Kothare S Piatt JH Jr Adirim TA 258 261 22 2006 16651918\n6 Chronic baclofen abuse and withdrawal delirium Aust N Z J Psychiatry Nasti JJ Brakoulias V 86 87 45 2011 21058925\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(5)", "journal": "Cureus", "keywords": "baclofen; delirium; oral; psychosis; withdrawal", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e14979", "pmc": null, "pmid": "34123673", "pubdate": "2021-05-12", "publication_types": "D002363:Case Reports", "references": "6711693;7435695;16651918;16288128;21058925", "title": "Oral Baclofen Withdrawal Resulting in Hyperactive Delirium: A Case Report.", "title_normalized": "oral baclofen withdrawal resulting in hyperactive delirium a case report" }	[ { "companynumb": "US-OXFORD PHARMACEUTICALS, LLC-2113360", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLPIDEM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "077088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Delirium", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Withdrawal syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SANDERS BJ, ALI Z. ORAL BACLOFEN WITHDRAWAL RESULTING IN HYPERACTIVE DELIRIUM: A CASE REPORT. CUREUS. 2021 MAY 12?13(5):E14979.", "literaturereference_normalized": "oral baclofen withdrawal resulting in hyperactive delirium a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210701", "receivedate": "20210701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19480901, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Paradoxical response (PR) in patients on anti-tuberculosis drugs and immune reconstitution inflammatory syndrome (IRIS) in patients started on antiretroviral therapy are well known phenomenon. We encountered a case of a paradoxical response in cerebral nocardiosis in a renal transplant recipient. To our knowledge this phenomenon in cerebral nocardiosis has not been reported earlier in literature.", "affiliations": "Consultant Internal Medicine and Infectious Diseases, Mumbai, Maharashtra.;Infectious Diseases Fellow, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.;Consultant Nephrologist, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.;Consultant Microbiology, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.;Consultant Microbiology, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.", "authors": "Soman\|Rajeev\|R\|;Koparkar\|Vidyullata\|V\|;Almeida\|Alan\|A\|;Shetty\|Anjali\|A\|;Rodrigues\|Camilla\|C\|", "chemical_list": null, "country": "India", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0004-5772", "issue": "66(9)", "journal": "The Journal of the Association of Physicians of India", "keywords": null, "medline_ta": "J Assoc Physicians India", "mesh_terms": "D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D016030:Kidney Transplantation; D009617:Nocardia Infections; D014376:Tuberculosis", "nlm_unique_id": "7505585", "other_id": null, "pages": "91-92", "pmc": null, "pmid": "31321940", "pubdate": "2018-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Paradoxical Response in Cerebral Nocardiosis in a Renal Transplant Recipient.", "title_normalized": "paradoxical response in cerebral nocardiosis in a renal transplant recipient" }	[ { "companynumb": "PHHY2018IN090285", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201109", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TMP?SMX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "40194", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40194", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201109", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201109", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20150920", "drugstartdateformat": "102", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20151010", "drugstartdateformat": "102", "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEFLAZACORT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201109", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEFLAZACORT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201109", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20150920", "drugstartdateformat": "102", "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEFLAZACORT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20150920", "drugstartdateformat": "102", "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEFLAZACORT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201109", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TMP?SMX" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin mass", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary nocardiosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Monoparesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20150920" } }, "primarysource": { "literaturereference": "SOMAN R, KOPARKAR V, ALMEIDA A, SHETTY A, RODRIGUES C. PARADOXICAL RESPONSE IN CEREBRAL NOCARDIOSIS IN A RENAL TRANSPLANT RECIPIENT. THE JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA. 2018?66:91?2", "literaturereference_normalized": "paradoxical response in cerebral nocardiosis in a renal transplant recipient", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20180911", "receivedate": "20180911", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15371451, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "Severe cutaneous adverse reactions (SCAR) to drugs are a crucial public health issue and the use of systemic corticosteroids in SCAR has been controversial.\nTo analyze clinical features, causative drugs, treatment, outcomes, and prognostic factors of SCAR in the case-series of 173 patients, and add more information to the debate of using systemic corticosteroids in SCAR management.\nA retrospective study of 173 SCAR patients diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) at a tertiary care institution in China between January 2014 and December 2017 was conducted.\nOf 173 patients, allopurinol, carbamazepine, and antibiotics are the most frequently implicated drugs for DRESS (40.4%), SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, there is a strongly negative correlation between early corticosteroids use and the progression (p=0.000) and severity (p=0.01) of skin lesions. However, there is no association between early corticosteroids use and the mortality of SCAR (odds ratio: 1.01, 95% confidence interval: 0.95~1.08). In addition, lymphadenopathy, eosinophilia, and interval from onset to corticosteroids treatment were correlated with SCAR prognosis.\nPrompt short-course systemic corticosteroids use is associated with early-stage skin lesions remission without influencing the disease mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR.", "affiliations": "Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.", "authors": "Xu\|Zhongyi\|Z\|https://orcid.org/0000-0001-8158-0825;Shen\|Jie\|J\|https://orcid.org/0000-0003-2504-4491;Yang\|Yiwen\|Y\|https://orcid.org/0000-0003-0145-7283;Yuan\|Ruoyue\|R\|https://orcid.org/0000-0001-6970-8611;Xiang\|Leihong Flora\|LF\|https://orcid.org/0000-0003-2080-0550;Zhang\|Chengfeng\|C\|https://orcid.org/0000-0002-1302-5667", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5021/ad.2019.31.5.545", "fulltext": "\n==== Front\nAnn Dermatol\nAnn Dermatol\nAD\nAnnals of Dermatology\n1013-9087\n2005-3894\nThe Korean Dermatological Association; The Korean Society for Investigative Dermatology\n\n10.5021/ad.2019.31.5.545\nOriginal Article\nSevere Cutaneous Adverse Reactions: A Single-Center Retrospective Study of 173 Patients in China\nhttps://orcid.org/0000-0001-8158-0825\nXu Zhongyi \nhttps://orcid.org/0000-0003-2504-4491\nShen Jie 1\nhttps://orcid.org/0000-0003-0145-7283\nYang Yiwen\nhttps://orcid.org/0000-0001-6970-8611\nYuan Ruoyue\nhttps://orcid.org/0000-0003-2080-0550\nXiang Leihong Flora\nhttps://orcid.org/0000-0002-1302-5667\nZhang Chengfeng\nDepartment of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.\n1 Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China.\nCorresponding author: Chengfeng Zhang, Department of Dermatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China. Tel: 86-02152889999, Fax: 86-02152887783, [email protected]\nThese two authors contributed equally to this work.\n\n10 2019\n30 8 2019\n31 5 545554\n30 5 2019\n09 7 2019\n15 7 2019\nCopyright © 2019 The Korean Dermatological Association and The Korean Society for Investigative Dermatology\n2019\nThe Korean Dermatological Association and The Korean Society for Investigative Dermatology\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nSevere cutaneous adverse reactions (SCAR) to drugs are a crucial public health issue and the use of systemic corticosteroids in SCAR has been controversial.\n\nObjective\n\nTo analyze clinical features, causative drugs, treatment, outcomes, and prognostic factors of SCAR in the case-series of 173 patients, and add more information to the debate of using systemic corticosteroids in SCAR management.\n\nMethods\n\nA retrospective study of 173 SCAR patients diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) at a tertiary care institution in China between January 2014 and December 2017 was conducted.\n\nResults\n\nOf 173 patients, allopurinol, carbamazepine, and antibiotics are the most frequently implicated drugs for DRESS (40.4%), SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, there is a strongly negative correlation between early corticosteroids use and the progression (p=0.000) and severity (p=0.01) of skin lesions. However, there is no association between early corticosteroids use and the mortality of SCAR (odds ratio: 1.01, 95% confidence interval: 0.95~1.08). In addition, lymphadenopathy, eosinophilia, and interval from onset to corticosteroids treatment were correlated with SCAR prognosis.\n\nConclusion\n\nPrompt short-course systemic corticosteroids use is associated with early-stage skin lesions remission without influencing the disease mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR.\n\nAcute generalized exanthematous pustulosis\nDrug reaction with eosinophilia and systemic symptoms\nStevens-Johnson syndrome\nSystemic corticosteroids treatment\nToxic epidermal necrolysis\nNational Natural Science Foundation of China https://doi.org/10.13039/501100001809 81573064 81472901 Shanghai Sailing Program 19YF1404800\n==== Body\nINTRODUCTION\n\nSevere cutaneous adverse reactions (SCAR) to drugs are among the most life-threatening conditions involving the skin, mainly encompassing drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP)1. DRESS is a hypersensitivity reaction, characterized by a variable combination of heterogenous clinical presentations2, such as fever, lymphadenopathy, eosinophilia, facial edema, erythroderma and even internal organ involvement3. SJS/TEN is known as a drug-induced hypersensitivity reaction, showing atypical target lesions and bullous lesions with acute exanthema. SJS and TEN are differentiated by the extent of epidermal detachment (SJS with body surface area [BSA] <10%, TEN with BSA >30%, and anything in-between called SJS-TEN overlap syndrome)4. AGEP is characterized by the rapid development of multiple non-follicular, sterile pustules on an erythematous base, mainly attributed to drugs, especially antibiotics, in the majority of cases5.\n\nGiven the severity of SCAR, numerous studies have been conducted. However, to date no specific treatment has been universally accepted. Meanwhile, information of SCAR patients in Asian population was extremely limited. In this retrospective study, we determined the reasons for administration in patients hospitalized with SCAR, the clinical pattern of reactions and the drugs causing adverse reactions in the biggest department of dermatology in China. Most notably, we aimed to examine the role of systemic corticosteroids in SCAR treatment and explore the potential prognostic factors of SCAR.\n\nMATERIALS AND METHODS\n\nPatient selection\n\nA retrospective review of electronic medical records was performed for all patients admitted to Department of Dermatology, Huashan Hospital as DRESS, SJS/TEN, and AGEP between January 2014 and December 2017. Inclusion criteria for this study required that patients met the diagnostic guidelines set by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR)6 for DRESS and SJS/TEN or the modified European Study of Severe Cutaneous Adverse Reactions (EuroSCAR) described by Sidoroff et al.7 for AGEP. No patients were lost to follow-up in this retrospective study. Informed consent was obtained from all patients to use their electronic medical data. The study protocol was approved by the Ethical Committee of Huashan Hospital (IRB no. KY2019-316).\n\nAssessment of drug causality\n\nThe drugs responsible for SCAR were defined as previously described67. The evaluation of drug causality was decided by a group of experienced dermatologists. In brief, if a drug was used continuously for more than three months, withdrawn for more than 14 days, or with a latent period less than three days, it would not be considered as the culprit drug for DRESS or SJS/TEN6. However, latent period for AGEP could be less than three days (typically within 48 hours or 24 hours for antibiotics)8. The “latent period” referred to the period from drug initiation to symptom onset. Moreover, previous use without a drug eruption history decreased suspicion, whereas an earlier reaction prioritized the drug. Hereafter, the remaining suspected drugs were re-evaluated based on the literature review. For cases with several suspected drugs remained, those with high notoriety were firstly considered (listed in Table 1) and those with low notoriety were marked as ‘possible’ (not listed in Table 1). Moreover, the sensitizing properties of different drugs were also taken into account.\n\nAssessment of SCAR outcomes\n\nClinical information with regards to demographic data, comorbidities, latency, and duration from onset to maximum BSA or BSA detachment (maximum BSA detachment for SJS/TEN and maximum BSA skin lesion involvement for DRESS and AGEP), maximum BSA or BSA detachment, time from onset to pharmacotherapy, co-administration of corticosteroids and intravenous immunoglobulin (IVIG) was recorded and analyzed. Outcomes analyzed for pharmacotherapy were progression of disease (defined as duration from the index day to maximum BSA or BSA detachment), severity of disease (maximum BSA or BSA detachment) and mortality. The 25th and 75th percentile of the time length of the lesions withdrawal by 50% were calculated, and prognosis were defined as good when 50% of the lesions withdrew less than seven days.\n\nStatistical analysis\n\nLinear regression analysis was applied to explore the association between the time from onset to corticosteroids treatment and progression of disease (duration from the index day to maximum BSA or BSA detachment) or severity of disease (maximum BSA or BSA detachment), while mortality analysis was based on logistic regression. Linear regression models were adjusted for age, sex, and disease classification (SJS/TEN, DRESS or AGEP) and co-administration of IVIG in order to take into account the confounding factors. In terms of prognostic factor analysis of SCAR, chi-squared test and one-way ANOVA were applied for univariate analysis. Then, the variables significantly associated with prognosis of SCAR in univariate analysis and the variables of great clinical concerns were further included in Cox regression analysis and enter selection was applied. The categorical variables were coded. The threshold for significance was set at p-value <0.05. All statistical analyses were performed using IBM SPSS Statistics ver. 21.0 software (IBM Corp., Armonk, NY, USA).\n\nRESULTS\n\nDemographics\n\nAs shown in Table 2, 173 SCAR patients were studied in this study. SJS/TEN was the most prevalent SCAR observed (55.5%, 96 cases), followed by DRESS (32.9%, 57 cases) and AGEP (11.6%, 20 cases). Males were predominant (1.48:1) in DRESS and females were predominant (0.54:1) in AGEP, whereas the number of males and females were similar for SJS/TEN. The mean period from drug initiation to symptom onset is 27.4 days for DRESS, 14.3 days for SJS/TEN, and 6.2 days for AGEP. The most common underlying diseases justifying the use of drugs were hyperuricemia or gout in DRESS, infection in SJS/TEN and AGEP.\n\nClinical characteristics\n\nThe clinical characteristics of the 173 SCAR patients were summarized in Table 3. Fever ≥38.5℃ was documented in 75% of DRESS patients, 83% of SJS/TEN patients and 50% of AGEP patients. Lymphadenopathy was observed in 63% and 23% of DRESS and SJS/TEN patients respectively. Notably, 19% DRESS patients, 2% SJS/TEN patients and 5% AGEP patients showed peripheral atypical lymphocytes. Leucocytosis was found in 63% of DRESS, 28% of SJS/TEN and 75% of AGEP patients. Leucocytopenia was infrequent, with only 23% in SJS/TEN. Neutrophilia was found in 47% of DRESS, 33% of SJS/TEN and 80% of AGEP patients. Monocytosis was prevalent in DRESS patients (35%) but not in SJS/TEN (16%) and AGEP (25%). Thrombocytosis was infrequent, with only 9% in DRESS and 7% in SJS/TEN patients. Thrombocytopenia was rare, with only 6% in SJS/TEN. Eosinophilia, defined as an absolute eosinophil count ≥700 U/L, was present in 77% of DRESS patients. While in SJS/TEN, only 9% of patients had an absolute eosinophil count ≥700 U/L.\n\nAll patients experienced an acute skin eruption. 91% of DRESS and SJS/TEN patients, and all of the AGEP patients had suggestive rash. The criteria for suggestive rash was facial edema or exfoliative dermatitis in DRESS, edematous erythema, target-like lesions, mucosal involvement, flaccid blisters, and exfoliation in SJS/TEN, and sterile nonfollicular pustules in AGEP6910. The rash was a monomorphic maculopapular in 28% of DRESS patients and only 2% of SJS/TEN patients, while in all other cases it was polymorphous, including variable combinations of other lesions. For example, DRESS patients usually had infiltrated plaques (95%), exfoliation (32%), purpura (26%), eczema-like lesions (19%), and blisters (16%). Whereas, SJS/TEN patients usually had exfoliation (92%), blisters (77%), target-like lesions (43%), and purpura (31%). Facial edema was observed in 86% of DRESS patients, 48% of SJS/TEN patients and 25% of AGEP patients. Mucosal involvement was recorded in 30% of DRESS patients and 94% of SJS/TEN patients. Most popular were oral lesions (21% of DRESS patients and 90% of SJS/TEN patients).\n\nIn terms of systemic involvement, most frequently the reaction affected the liver (95% of DRESS patients, 72% of SJS/TEN patients, and 30% of AGEP patients), followed by kidney (46% of DRESS patients, 55% of SJS/TEN patients, and 5% of AGEP patients) and lung (21% of DRESS patients and 15% of SJS/TEN patients).\n\nCausative drugs\n\nIn this study, two DRESS patients (3.5%), eight SJS/TEN patients (8.3%), and three AGEP patients (15.0%) were not exposed to any medication according to the criteria of culprit drugs in RegiSCAR6 or modified EuroSCAR for AGEP7. As for other SCAR cases, the summary of drug causality was presented in Table 1. In addition, we categorized all SCAR cases by causative drugs into three groups: allopurinol group, carbamazepine group, and other causative drugs group. Univariate analysis of the outcome measures showed difference in the severity of SCAR (p=0.031) but no difference in the progression of SCAR among three causative drugs groups. Further two-two comparisons also showed that the difference between allopurinol group and carbamazepine group (p=0.039) and the difference between carbamazepine group and other causative drugs group were statistically significant (p=0.010). However, when stratified by disease types, causative drugs showed difference only in the severity of SJS/TEN, whereas no differences in the severity of DRESS or AGEP.\n\nTreatment\n\nIn our observational study, 56 DRESS patients (98.2%), 96 SJS/TEN patients (100.0%), and 20 AGEP patients (100.0%) received systemic corticosteroids. Intravenous methylprednisolone was given at 1~1.5 mg/kg/d. Once the progression of the disease was halted, which manifested as no new lesions, Nikolsky sign turning negative, exudation improved, re-epithelialization and laboratory test results being stable, the dose of corticosteroids was tapered promptly. Meanwhile, 43 DRESS patients (75.4%), 88 SJS/TEN patients (91.6%), and four AGEP patients (20.0%) received treatment with IVIG. IVIG was administered at 0.4 g/kg/d for over 5 days. Univariate analysis of the outcome measures showed that early use of systemic corticosteroids was significantly and negatively related to the progression of SCAR (p=0.000) and the severity of SCAR (p=0.001). Further multivariate analysis also indicated the negative linear association of early use of systemic corticosteroids and the progression (p=0.000) and the severity of SCAR (p=0.01) (Table 4). Duration from onset to maximum BSA or BSA detachment will be 0.858-day longer when the initiation of systemic corticosteroids was delayed for 1 day (Table 4). It means later systemic corticosteroids use might prolong the duration of active stage SCAR, and it would take more time for SCAR patients to reach stable stage (no new lesions). Moreover, one-day delay of the systemic corticosteroids use would increase 19.2% of maximum BSA or BSA detachment (Table 4). In contrast, IVIG treatment did not statistically affect the primary outcomes of both the disease progression and severity. Among all 173 SCAR patients, none of them died during their stay in hospital, and only two DRESS patients (3.5%), four SJS/TEN patients (4.2%) and no AGEP patient died in the first three months after discharge. Both two DRESS patients died of lung infection. Three SJS/TEN patients died of multiple organ dysfunction syndrome, and one SJS/TEN patients died of lactic acidosis. For mortality analysis, no statistical difference was revealed between early and delayed systemic corticosteroids use (odds ratio [OR]: 1.01, 95% confidence interval [CI]: 0.95~1.08) (Table 5).\n\nPrognostic factors of SCAR\n\nFollowing risk factors were included in the regression model to analyze their associations with SCAR: disease type, age, sex, lymphadenopathy, eosinophilia, mucosal involvement, internal organ involvement, interval from onset to standard treatment with adequate corticosteroids, combination therapy with IVIG, and causative drugs (Table 6). Multivariate analysis showed disease type (p=0.035), lymphadenopathy (p=0.001), eosinophilia (p=0.019) and interval from onset to standard treatment with adequate corticosteroids (p=0.000) were the independent risk factors for the prognosis of SCAR. Patients with lymphadenopathy had longer time for 50% lesions' withdrawal than those with no lymphadenopathy (OR: 2.356, 95% CI: 1.433~3.875). Moreover, when we categorized eosinophilia into three groups: moderate (<700), high (700~1,500) and higher (>1,500), high levels of eosinophilia proved to be a poor prognosis factor of SCAR, with 2-fold higher risks of longer lesions' withdrawal time (high, OR: 2.709, 95% CI: 1.283~5.721; higher, OR: 2.133, 95% CI: 1.059~4.296), compared with moderate eosinophilia level. Furthermore, interval from onset to standard treatment with adequate corticosteroids was proved to be a protective factor for the prognosis of SCAR (OR: 0.963, 95% CI: 0.943~0.983). However, mucosal involvement, internal organ involvement, co-treatment with IVIG and SCAR causative drug types were not independent prognostic factors for SCAR.\n\nDISCUSSION\n\nPrevious studies showed conflicting results about the incidence of SCAR in different genders. In our study, DRESS occurred more common in male than female. It might be due to the fact that 40.4% DRESS cases had underlying hyperuricemia or gout, which is much more prevalent in men as well11. Whereas in SJS/TEN and AGEP, infection (28.1% for SJS/TEN and 45.0% for AGEP) was the most common underlying disease, which was consistent with previous study12.\n\nAccording to our data, internal organ involvement (98%), facial edema (86%), eosinophilia (77%), high fever (75%), leukocytosis (63%), and lymphadenopathy (63%) were characteristic for DRESS. As for SJS/TEN, the main features next to the ubiquitous exanthema were mucosal involvement (94%), internal organ involvement (89%), fever (83%), and neutrophilia (33%). As for AGEP, the main features were pustules (100%), neutrophilia (80%), leukocytosis (75%), and fever (50%). Notably, our findings revealed that 46 SJS/TEN patients (48%) had facial edema, which was quite different from the traditional concept that facial edema was the warning signal for DRESS and rarely occurred in other SCAR6. We considered that diffuse erythema on face in combination with mucosal involvement like conjunctivae or lips13 could manifest as facial edema in severe SJS/TEN cases. Additionally, 17 DRESS patients (30%) had mucosal involvement, which was similar as previous reported3. Nine SJS/TEN patients (9%) had increased peripheral eosinophil counts, which highlighted that eosinophilia could occur in SCAR other than DRESS14. Some studies even reported that eosinophilia was associated with poor SCAR outcomes151617. Higher percentage of lymphadenopathy in DRESS (63%) than other SCAR was similar to previous studies, which would be explained by the potential activation of virus infections, such as Epstein-Barr virus, cytomegalovirus or human herpesvirus 6 in DRESS181920. Six AGEP (30%) had internal organ involvement, which was similar to previous studies that AGEP-specific hepatitis, nephritis or pneumonia were rare but sometimes occurred2122. Thus, systemic investigations were recommended for all SCAR types.\n\nOver the past few decades, important progress has been made in understanding the pathogenesis of SJS/TEN, especially the role of human leukocyte antigen (HLA) alleles2324. Antiepileptic agents (phenobarbital, carbamazepine, phenytoin, and lamotrigine), minocycline, allopurinol, dapsone, and sulfonamides are the most frequently reported causative drugs of DRESS2526. In our study, the most common culprit drug for DRESS was allopurinol. HLA-B 58:01 has been reported to be associated with allopurinol-induced SCAR27. As for carbamazepine, the leading causative drug for SJS/TEN in our study, HLA-B 15:02 was responsible for carbamazepine-induced SJS/TEN28, and HLA-A 31:01 showed a stronger correlation with carbamazepine-induced DRESS29. Antibiotics were the leading cause of AGEP in our findings, which was also in agreement with previous reports30. However, further studies are required with regard to the limited number of AGEP patients in our study. Notably, 5.3% DRESS, 8.3% SJS/TEN, and 30.0% AGEP cases were caused by traditional Chinese medicine (TCM) use. The associated TCMs were radix isatidis, propolis, scolopendra, salvianolate, sophora flavescens, berberine, paraquat, Leonurus artemisia, bezoar, berberine, notoginseng triterpenes, Cordyceps sinensis, and Platycarya strobilacea. Among those listed, only paraguat has been reported to cause TEN31, and propolis has been reported to cause fixed drug eruption32. All other TCMs were newly reported. Considering the popular application of TCM treatment in Asian cultures, connection between TCM and SCAR needs to be further clarified. In our study, there were still a small number of SCAR cases with no culprit drugs, which was in accordance with previous studies that SCAR could attribute to exposures other than medications, such as infection, foods or transplantation33.\n\nSystemic corticosteroids have long been regarded as the mainstay treatment for SCAR. However it is still controversial how much benefit patients would get from this treatment. Some case series have concluded that the use of systemic steroids were beneficial in reducing morbidity and mortality3435, whereas others suggesting minimal or no benefit in terms of outcome363738. Some earlier observational studies even indicated an increased mortality and a higher frequency of complications for TEN patients treated with systemic steroids394041. Here, we reveal that early steroids therapy could alleviate the severity (p=0.01) and progression (p=0.000) of SCAR without influencing the mortality rate. These results suggest that early shortcourse steroids use is helpful in the initial phase management of SCAR at least in a modern well-equipped tertiary care hospital. Since more than 98.2% SCAR cases received systemic steroids, we could not demonstrate the difference of outcomes with and without systemic steroids use. Further studies with different therapy are required to answer this question.\n\nSCARs are associated with significant morbidity, mortality, and socioeconomic costs. Predicting outcomes for each specific SCAR patient at an early stage would be extremely helpful for physicians to formulate appropriate treatment strategy. However, very few clinical researches have focused on the prognostic factors of SCAR1516174243. According to our results, lymphadenopathy and eosinophilia were associated with a poor outcome. The role of eosinophilia in the outcomes of SCAR has been reported before151617, while lymphadenopathy as a poor prognostic factor for SCAR was reported for the first time. This can be explained by the potential activation of virus infections, such as Epstein-Barr virus, cytomegalovirus or human herpesvirus 6181920.\n\nLimitations of the study included the retrospective design and a predominance of Asian population. Since most SCAR patients in our study had received systemic corticosteroids in combination with IVIG, further case-control studies with larger sample size are required for more detailed research. In addition, there have been no universal rules that could determine the causative drug of SCAR with certainty, and the rule used in this study is imperfect as well. Moreover, the long-term follow-up of SCAR patients post-discharge was lacking. However, due to the fact that the ultimate prospective blinded study needed to provide a more definitive answer to the questions about steroid use in SCAR management is extremely difficult to do, our study is of significance in guiding clinical practice. In conclusion, allopurinol, carbamazepine, and antibiotics were the most frequent implicated drugs for DRESS, SJS/TEN, and AGEP respectively. Hyperuricemia or gout was the most frequent cause of administration in DRESS, and infection was that in SJS/TEN and AGEP. Selection and prescription of those drugs should be more cautiously. Additionally, early initiation of steroids might help prevent the progression of skin lesions and decrease the severity of skin lesions or skin detachment, but had no correlation with mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR. For SCAR patients with lymphadenopathy and eosinophilia, physicians may consider taking a more aggressive therapeutic approach.\n\nACKNOWLEDGMENT\n\nThis work was supported by grants from Natural Science Foundation of China (No. 81573064 and 81472901) and Shanghai Sailing Program (No. 19YF1404800).\n\nWe thank Prof. Xiaoqun Luo for her critical reading, and thank Dr. Shengan Chen and Xiaojin Wu for their excellent technical assistance.\n\nTable 1 Causative drugs of SCAR\n\nAssociated drug\tCase (%)\t\nDRESS\t\t\n Allopurinol\t23 (40.4)\t\n Sulfasalazine\t8 (14.0)\t\n Phenobarbital\t4 (7.0)\t\n Carbamazepine\t4 (7.0)\t\n Mexiletine\t3 (5.3)\t\n Antibiotics (antifungals)\t4 (7.0)\t\n Cephalosporin (cefprozil, cefoxitin)\t2\t\n Amoxicillin\t1\t\n Fluconazole\t1\t\n TCM (radix isatidis, propolis, herbs)\t3 (5.3)\t\n Indomethacin\t2 (3.5)\t\n Other drugs\t4 (7.0)\t\nSJS/TEN\t\t\n Carbamazepine\t25 (26.0)\t\n Antibiotics\t15 (15.6)\t\n Cephalosporin (cefotaxime, cefmetazole, cefotiam, cefprozil, cefepime)\t6\t\n Levofloxacin\t4\t\n Metronidazole\t2\t\n Amoxicillin\t1\t\n Clarithromycin\t1\t\n Erythromycin\t1\t\n Allopurinol\t11 (11.5)\t\n TCM (berberine, bezoar, leonurus artemisia, paraquat, radix isatidis, salvianolate, scolopendra, sophora flavescens)\t8 (8.3)\t\n Methazolamide\t5 (5.2)\t\n Compound paracetamol and amantadine\t4 (4.2)\t\n Edaravone\t2 (2.0)\t\n Phenytoin\t2 (2.0)\t\n Sulfasalazine\t2 (2.0)\t\n Valaciclovir\t2 (2.0)\t\n Valproate\t2 (2.0)\t\n Other drugs†\t10 (10.4)\t\nAGEP\t\t\n Antibiotics\t8 (40.0)\t\n Cephalosporin (cefaclor, cefotiam, cefepime)\t3\t\n Clindamycin\t2\t\n Azithromycin\t1\t\n Levofloxacin\t1\t\n Isepamicin\t1\t\n TCM (notoginseng triterpenes, radix isatidis, Cordyceps sinensis)\t6 (30.0)\t\n NSAIDS\t2 (10.0)\t\n Paracetamol\t1\t\n Meloxicam\t1\t\n Urea C 14\t1 (5.0)\t\nSCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, TCM: traditional chinese medicine, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, NSAIDS: nonsteroidal anti-inflammatory drugs. Compound paracetamol and amantadine, flunarizine, oxcarbazepine, and phenytoin. †Amlodipine, dabigatran, fentanyl, ossotide, paracetamol, phenobarbital, pyrazinamide, rabeprazole, tetanus antitoxin, and tropicamide.\n\nTable 2 Demographics\n\n\tDRESS (n=57)\tSJS/TEN (n=96)\tAGEP (n=20)\t\nSex ratio (male/female)\t1.48 (34/23)\t1 (48/48)\t0.54 (7/13)\t\nAge (yr)\t50.5 (32.3~66)\t51.5 (31.8~65)\t36 (31.3~55)\t\nLatent period (d)\t27.4±4.3\t14.3±2.1\t6.2±2.4\t\nUnderlying disease\t\t\t\t\n Hyperuricemia/gout\t23 (40.4)\t11 (11.5)\t-\t\n Infection†\t8 (14.0)\t27 (28.1)\t9 (45.0)\t\n Inflammatory disease‡\t8 (14.0)\t2 (2.1)\t2 (10.0)\t\n Seizure/paralysis/spasm\t7 (12.3)\t15 (15.6)\t-\t\n Pain§\t5 (8.8)\t14 (14.6)\t3 (15.0)\t\n Others\t5 (8.8)\t19 (19.8)\t3 (15.0)\t\nValues are presented as ratio, median (interquartile range), mean±standard deviation, or number (%). DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, -: not applicable. The period from drug initiation to symptom onset. †DRESS: respiratory infection (5 cases), vaginitis (1 case), nasosinusitis (1 case), gastroenteritis (1 case). SJS/TEN: respiratory infection (8 cases), eye infection (5 cases), vaginitis (3 cases), duodenal ulcer with Helicobacter pylori infection (2 cases), sepsis (2 cases), cervicitis (2 cases), skin infection (2 cases), gastroenteritis (1 case), tuberculosis (1 case). AGEP: respiratory infection (2 cases), cholecystitis (1 case), gastroenteritis (2 cases), otitis (2 cases), nasosinusitis (1 case), urocystitis (1 case). ‡DRESS: ankylosing spondylitis (4 cases), osteoarthritis (1 case), Crohn's disease (1 case), rheumatic arthritis (1 case), ulcerative colitis (1 case). SJS/TEN: ulcerative colitis (2 cases). AGEP: rheumatic arthritis (1 case), periarthritis humeroscapularis (1 case). §DRESS: neuralgia (2 case), headache (1 case), post-surgery pain (1 case), pharyngalgia (1 case). SJS/TEN: postherpetic neuralgia (5 cases), trigeminal neuralgia (3 cases), headache (3 cases), pharyngalgia (1 case), neuralgia (1 case), and post-surgery pain (1 case). AGEP: pharyngalgia (3 cases).\n\nTable 3 Clinical characteristics\n\nCharacteristic\tDRESS (n=57)\tSJS/TEN (n=96)\tAGEP (n=20)\t\nn\t95% CI\tn\t95% CI\tn\t95% CI\t\nFever ≥38.5℃\t43\t75 (63~85)\t80\t83 (75~89)\t10\t50 (30~70)\t\nLymphadenopathy\t36\t63 (50~74)\t22\t23 (16~32)\t2\t10 (3~30)\t\nAtypical lymphocytes\t11\t19 (11~31)\t2\t2 (0~7)\t1\t5 (1~24)\t\nLeucocytosis\t36\t63 (50~74)\t27\t28 (20~38)\t15\t75 (53~89)\t\nLeucocytopenia\t0\t-\t22\t23 (16~32)\t0\t-\t\nNeutrophilia\t27\t47 (35~60)\t32\t33 (25~43)\t16\t80 (58~92)\t\nLymphocytosis\t0\t-\t0\t-\t0\t-\t\nMonocytosis\t20\t35 (24~48)\t15\t16 (10~24)\t5\t25 (11~47)\t\nThrombocytosis\t5\t9 (4~19)\t7\t7 (4~14)\t0\t-\t\nThrombocytopenia\t0\t-\t6\t6 (3~13)\t1\t5 (1~24)\t\nEosinophilia\t44\t77 (65~86)\t9\t9 (5~17)\t1\t5 (1~24)\t\nGrade 1\t11\t19 (11~31)\t7\t7 (4~14)\t1\t5 (1~24)\t\nGrade 2\t33\t58 (45~70)\t2\t2 (0~7)\t0\t-\t\nExtent of rash >50%\t56\t98 (91~100)\t95\t99 (94~100)\t17\t85 (64~95)\t\nSuggestive rash\t52\t91 (81~96)\t87\t91 (83~95)\t20\t100 (84~100)\t\nFacial edema\t49\t86 (75~93)\t46\t48 (38~58)\t5\t25 (11~47)\t\nMonomorphic maculopapular\t16\t28 (18~41)\t2\t2 (0~7)\t0\t-\t\nPolymorphous maculopapular\t40\t70 (57~80)\t94\t98 (93~99)\t20\t100 (84~100)\t\nUrticarial\t0\t-\t0\t-\t1\t5 (1~24)\t\nExfoliative\t18\t32 (21~44)\t88\t92 (84~96)\t1\t5 (1~24)\t\nLichenoid\t1\t2 (0~9)\t0\t-\t0\t-\t\nPustules\t0\t-\t1\t1 (0~6)\t20\t100 (84~100)\t\nPurpura\t15\t26 (17~39)\t30\t31 (23~41)\t4\t20 (8~41)\t\nInfiltrated plaques\t54\t95 (86~98)\t41\t43 (33~53)\t13\t65 (54~82)\t\nBlisters\t9\t16 (9~27)\t74\t77 (68~84)\t3\t15 (5~36)\t\nTarget-like lesions\t4\t7 (3~17)\t41\t43 (33~53)\t4\t20 (8~41)\t\nEczema-like lesions\t11\t19 (11~31)\t3\t3 (1~9)\t3\t15 (5~36)\t\nMucosal involvement\t17\t30 (20~43)\t90\t94 (86~97)\t0\t-\t\nMouth/throat/lips\t12\t21 (12~33)\t87\t90 (83~95)\t0\t-\t\n Eyes\t3\t5 (2~14)\t53\t55 (45~65)\t0\t-\t\n Genitalia\t9\t16 (9~27)\t69\t72 (62~80)\t0\t-\t\n Other\t1\t2 (0~9)\t21\t22 (15~31)\t0\t-\t\nInternal organ involvement\t56\t98 (91~100)\t85\t89 (81~93)\t6\t30 (15~52)\t\n 1 Organ involved\t16\t28 (18~41)\t36\t38 (28~47)\t5\t25 (11~47)\t\n 2 Organs involved\t30\t53 (40~65)\t31\t32 (24~42)\t1\t5 (1~24)\t\n >2 Organs involved\t10\t18 (10~29)\t18\t19 (12~28)\t0\t-\t\n Liver\t54\t95 (86~98)\t69\t72 (62~80)\t6\t30 (15~52)\t\n Kidney\t26\t46 (33~58)\t53\t55 (45~65)\t1\t5 (1~24)\t\n Lung\t12\t21 (12~33)\t14\t15 (9~23)\t0\t-\t\n Muscle/heart\t9\t16 (9~27)\t18\t19 (12~28)\t1\t5 (1~24)\t\n Spleen\t5\t9 (4~19)\t1\t1 (0~6)\t0\t-\t\n Pancreas\t1\t2 (0~9)\t5\t5 (2~12)\t0\t-\t\n Other\t0\t-\t1\t1 (0~6)\t0\t-\t\nLeucocytosis >10,000 U/L, Leucocytopenia <4,000 U/L, Neutrophilia >7,000 U/L, Lymphocytosis >4,000 U/L, Monocytosis >1,000 U/L, Thrombocytosis >400,000 U/L, Thrombocytopenia <100,000 U/L, Eosinophilia Grade 1: 700~1,499 U/L, Eosinophilia Grade 2: >1,500 U/L. DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, -: stands for not applicable. Liver: elevation of liver enzymes (twice the normal value), kidney: elevation of creatinine (twice the normal value) or the occurrence of proteinuria or hematuria, lung: inflammation or interstitial change on X-ray or computerized tomography (CT), muscle: elevation of creatine kinase (CK), heart: elevation of CK-muscle/brain or myoglobin, spleen: splenomegaly reported on ultrasound or CT, pancreas: elevation of serum/uric amylase or lipase, or pancreatic edema reported on CT.\n\nTable 4 Linear regression of SCAR progression and severity (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)\n\n\tUnadjusted linear regression\tAdjusted linear regression\t\nStandardized coefficients β\tp-value\tStandardized coefficients β\tp-value\t\nDuration from onset to maximum BSA or BSA detachment\t\t\t\t\t\n Time from onset to corticosteroids treatment\t0.857\t0.000\t0.858\t0.000\t\n Classification\t\t\t\t\t\n AGEP\t0\t\t0\t\t\n DRESS\t0.285\t0.02\t0.022\t0.758\t\n SJS/TEN\t0.158\t0.195\t0.04\t0.599\t\n Age (yr, linear)\t−0.002\t0.952\t0.011\t0.790\t\n Sex\t0.019\t0.802\t−0.069\t0.085\t\n IVIG\t0.166\t0.029\t0.052\t0.274\t\nMaximum BSA or BSA detachment\t\t\t\t\t\n Time from onset to corticosteroids treatment\t0.0244\t0.001\t0.192\t0.010\t\n Classification\t\t\t\t\t\n AGEP\t0\t\t0\t\t\n DRESS\t0.14\t0.232\t0.099\t0.442\t\n SJS/TEN\t−0.212\t0.07\t−0.225\t0.100\t\n Age (yr, linear)\t−0.108\t0.156\t−0.097\t0.180\t\n Sex\t−0.015\t0.846\t−0.055\t0.445\t\n IVIG\t−0.047\t0.542\t0.026\t0.759\t\nMaximum BSA for AGEP and DRESS, and maximum BSA detachment for SJS/TEN. SCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, BSA: body surface area, IVIG: intravenous immunoglobulin.\n\nTable 5 Logistic regression of mortality (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)\n\n\tUnadjusted logistic regression OR (95% CI)\tAdjusted logistic regression OR (95% CI)\t\nDuration from onset to maximum BSA or BSA detachment\t\t\t\n Time from onset to corticosteroids treatment\t1.01 (0.95~1.08)\t1.02 (0.97~1.09)\t\n Classification\t\t\t\n DRESS\t0.77 (0.14~4.36)\t0.77 (0.13~4.72)\t\n SJS/TEN\t1 1\t\t\n Age (yr, linear)\t1.08 (1.02~1.16)\t1.08 (1.01~1.16)\t\n Sex\t1.85 (0.33~10.41)\t1.58 (0.26~9.49)\t\nMaximum BSA for AGEP and DRESS, and maximum BSA detachment for SJS/TEN. DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, OR: odds ratio, CI: confidence interval, BSA: body surface area.\n\nTable 6 Prognostic factors of SCAR (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)\n\nCovariate\tUnivariate\tMultivariate\t\np-value\tB\tExp (B) (95% CI)\tp-value\t\nDisease type\t0.001\t\t\t0.035\t\n SJS/TEN\t\t\t\t\t\n AGEP\t0.001\t0.717\t2.048 (0.674~6.224)\t0.206\t\n DRESS\t0.046\t−0.683\t0.505 (0.228~1.116)\t0.091\t\nSex\t0.21\t0.297\t1.346 (0.919~1.971)\t0.127\t\nAge (yr)\t\t0\t1.000 (0.989~1.011)\t0.975\t\nLymphadenopathy\t0.025\t0.857\t2.356 (1.433~3.875)\t0.001\t\nEosinophilia\t0.021\t\t\t0.019\t\n <700\t\t\t\t\t\n 700~1,500\t0.01\t0.997\t2.709 (1.283~5.721)\t0.009\t\n >1,500\t0.127\t0.757\t2.133 (1.059~4.296)\t0.034\t\nMucosal involvement\t0.001\t0.207\t1.231 (0.635~2.385)\t0.539\t\nInternal organ involvement\t0.187\t\t\t0.405\t\n No organ involved\t\t\t\t\t\n 1 Organ involved\t0.171\t0.491\t1.633 (0.732~3.644)\t0.231\t\n 2 Organs involved\t0.058\t0.154\t1.166 (0.535~2.540)\t0.699\t\n 3 And more organs involved\t0.046\t0.193\t1.213 (0.523~2.812)\t0.653\t\nInterval from onset to corticosteroids treatment\t\t−0.038\t0.963 (0.943~0.983)\t0.000\t\nIVIG\t0\t−0.36\t0.698 (0.401~1.214)\t0.203\t\nCausative drugs\t0.37\t\t\t0.293\t\n Allopurinol\t\t\t\t\t\n Carbamazepine\t0.161\t\t0.706 (0.391~1.274)\t0.248\t\n Others\t0.35\t\t0.677 (0.412~1.113)\t0.124\t\nSCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, IVIG: intravenous immunoglobulin.\n\nCONFLICTS OF INTEREST: The authors have nothing to disclose.\n==== Refs\n1 Roujeau JC Stern RS Severe adverse cutaneous reactions to drugs N Engl J Med 1994 331 1272 1285 7794310\n2 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Semin Cutan Med Surg 1996 15 250 257 9069593\n3 Kardaun SH Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? 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CJ Ho HC Yang CH Lin YJ Identifying prognostic factors for drug rash with eosinophilia and systemic symptoms (DRESS) Eur J Dermatol 2011 21 930 937 21951554\n43 Bastuji-Garin S Fouchard N Bertocchi M Roujeau JC Revuz J Wolkenstein P SCORTEN: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol 2000 115 149 153 10951229\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1013-9087", "issue": "31(5)", "journal": "Annals of dermatology", "keywords": "Acute generalized exanthematous pustulosis; Drug reaction with eosinophilia and systemic symptoms; Stevens-Johnson syndrome; Systemic corticosteroids treatment; Toxic epidermal necrolysis", "medline_ta": "Ann Dermatol", "mesh_terms": null, "nlm_unique_id": "8916577", "other_id": null, "pages": "545-554", "pmc": null, "pmid": "33911647", "pubdate": "2019-10", "publication_types": "D016428:Journal Article", "references": "22639874;22828258;20713773;28911824;25592341;12164739;17300272;17340021;22002792;20605253;10951229;9069593;21428769;15743917;17854366;26228174;17919775;26481651;20548906;26354880;7145729;28476287;3767483;23855313;23132554;7487252;7794310;28718873;23866879;20542841;13679697;23855377;21800283;7874336;24749495;11168761;27075126;24597466;23602183;26769645;21204807;28867742;21951554", "title": "Severe Cutaneous Adverse Reactions: A Single-Center Retrospective Study of 173 Patients in China.", "title_normalized": "severe cutaneous adverse reactions a single center retrospective study of 173 patients in china" }	[ { "companynumb": "CN-JNJFOC-20191011689", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TETANUS ANTITOXIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "XU Z, YANG Y, YUAN R, XIANG L, ZHANG C, SHEN J. SEVERE CUTANEOUS ADVERSE REACTIONS: A SINGLE-CENTER RETROSPECTIVE STUDY OF 173 PATIENTS IN CHINA. ANNALS OF DERMATOLOGY 2019. 2019?31(5):545-554.", "literaturereference_normalized": "severe cutaneous adverse reactions a single center retrospective study of 173 patients in china", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20191022", "receivedate": "20191022", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16943545, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "CN-JNJFOC-20191027562", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "XU Z, YANG Y, YUAN R, XIANG L, ZHANG C, SHEN J, XU Z. SEVERE CUTANEOUS ADVERSE REACTIONS: A SINGLE-CENTER RETROSPECTIVE STUDY OF 173 PATIENTS IN CHINA. ANNALS OF DERMATOLOGY 2019. 2019?31(5):545-554.", "literaturereference_normalized": "severe cutaneous adverse reactions a single center retrospective study of 173 patients in china", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20191021", "receivedate": "20191021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16941495, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]
{ "abstract": "The nucleus tractus solitarius and paratrigeminal nucleus, which are implicated in the processing of airway-derived sensory information, are found in the dorsal medulla. The mechanism and localization of higher-order processing of urge to cough is poorly understood, and much of the existing anatomical localization is limited to animal studies.\n\n\n\nA 44-year-old Caucasian lady underwent elective foramen magnum decompression for symptomatic Chiari I malformation; postoperatively she had resolution of Chiari symptoms but developed an intractable neurogenic cough. She has no significant medical history or premorbid respiratory issues. Postoperative magnetic resonance imaging of her head demonstrated signal change in the left dorsal medulla, corresponding with the nucleus tractus solitarius and paratrigeminal nucleus.\n\n\n\nWe suggest that this lesion explains her isolated new cough and localizes the pathway for \"urge to cough\" to this region of the medulla.", "affiliations": "Department of Neurosurgery, Royal Victoria Hospital, Newcastle, UK. Electronic address: [email protected].;Department of Neurosurgery, Royal Victoria Hospital, Newcastle, UK.", "authors": "Paranathala\|Menaka Pasangy\|MP\|;Mitchell\|Patrick\|P\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.wneu.2020.09.096", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-8750", "issue": "144()", "journal": "World neurosurgery", "keywords": "Case report; Medulla; Neurogenic cough; Nucleus tractus solitarius; Paratrigeminal nucleus; Urge-to-cough; Vagus", "medline_ta": "World Neurosurg", "mesh_terms": "D000328:Adult; D001139:Arnold-Chiari Malformation; D003371:Cough; D019299:Decompression, Surgical; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008526:Medulla Oblongata; D019635:Neurosurgical Procedures; D011183:Postoperative Complications; D016896:Treatment Outcome", "nlm_unique_id": "101528275", "other_id": null, "pages": "196-198", "pmc": null, "pmid": "32977030", "pubdate": "2020-12", "publication_types": "D002363:Case Reports", "references": null, "title": "Neurogenic Cough Associated with Hyperintensity in Dorsal Medulla: Case Report and Anatomical Discussion.", "title_normalized": "neurogenic cough associated with hyperintensity in dorsal medulla case report and anatomical discussion" }	[ { "companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-272602", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAZOLAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAZOLAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202637", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR 5 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COUGH", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PARANATHALA MP, MITCHELL P. NEUROGENIC COUGH ASSOCIATED WITH HYPERINTENSITY IN DORSAL MEDULLA: CASE REPORT AND ANATOMICAL DISCUSSION. WORLD NEUROSURG. 2020?DEC(144):196-198", "literaturereference_normalized": "neurogenic cough associated with hyperintensity in dorsal medulla case report and anatomical discussion", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20201224", "receivedate": "20201224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18657179, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]
{ "abstract": "Tiopronin (TP), a glycine derivative with a free thiol, is extensively used for the treatment of cystinuria. Moreover, TP is usually prescribed as hepatoprotective medicine in China. In the present case, a 36-year-old female who presented with foamy urine and general edema was admitted to the hospital. She had been taking TP for six months to treat drug-induced liver injury due to anti-tuberculosis drugs including isoniazid, rifampicin and pyrazinamide. The urine tests at admission revealed nephritic-range proteinuria with a daily urinary protein level of 8,024 mg. Meanwhile, albumin and cholesterol levels were abnormal. The light microscopy was negative and electron microscopy showed foot process effacement. Thus, minimal change disease (MCD) was diagnosed, and TP was consequently discontinued. Finally, the patient accomplished complete remission within five weeks after the cessation of TP without undergoing glucocorticoid therapy. TP was speculated to play an antigenic role in this adverse effect. To date, there are only two similar cases documented in the literature. Herein, we first report a case of a Chinese patient who generated MCD after prolonged TP administration. Clinicians should be wary of the occurrence of MCD due to TP when administering long-term therapy of TP. A weekly urinalysis may be useful for early identification of TP-induced MCD.", "affiliations": "Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.", "authors": "Zhong\|Han\|H\|;Wang\|Ling\|L\|;Gu\|Zhi-Chun\|ZC\|;Cui\|Min\|M\|;Liu\|Xiao-Yan\|XY\|;Pang\|Xiao-Yun\|XY\|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/atm.2019.07.42", "fulltext": null, "fulltext_license": null, "issn_linking": "2305-5839", "issue": "7(16)", "journal": "Annals of translational medicine", "keywords": "Minimal change disease (MCD); adverse drug reaction; nephrotic syndrome (NS); tiopronin (TP)", "medline_ta": "Ann Transl Med", "mesh_terms": null, "nlm_unique_id": "101617978", "other_id": null, "pages": "398", "pmc": null, "pmid": "31555712", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": "10073167;11494716;15602663;15865542;2057710;20924604;21297330;2138812;2225561;2250412;23631305;24190152;24488902;25026975;25296595;25684013;26330362;2812476;29851774;30051231;3516496;3873945;470014;7158085;7249508;748588;8162007;8242033;9796255", "title": "Minimal change disease induced by tiopronin: a rare case report and a review of the literature.", "title_normalized": "minimal change disease induced by tiopronin a rare case report and a review of the literature" }	[ { "companynumb": "CN-MICRO LABS LIMITED-ML2019-02765", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TIOPRONIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG THREE TIMES DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNEVALUABLE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201609", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOPRONIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205600", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG QD PO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG QD PO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PASINIAZID" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG TID PO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PASINIAZID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG ORALLY TWICE WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glomerulonephritis minimal lesion", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZHONG H, WANG L, GU Z, CUI M, LIU X, PANG X. MINIMAL CHANGE DISEASE INDUCED BY TIOPRONIN: A RARE CASE REPORT AND A REVIEW OF THE LITERATURE. ANNALS OF TRANSLATIONAL MEDICINE. 2019?7 NO.16:.", "literaturereference_normalized": "minimal change disease induced by tiopronin a rare case report and a review of the literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20191023", "receivedate": "20191023", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16949052, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]
{ "abstract": "Bilateral intraocular inflammation and simultaneous development of tattoo granulomas has been described in several case reports. The pathophysiology of this process is poorly understood, and it has been hypothesized that it could be a similar mechanism to systemic sarcoidosis versus a delayed hypersensitivity response. Granulomatous tattoo reaction with associated uveitis can manifest with or without evidence of systemic sarcoidosis, and it is usually responsive to immunosuppression and/or tattoo removal. We present a patient with no prior diagnosis of sarcoidosis who developed bilateral panuveitis and tattoo changes suggestive of tattoo granulomas with uveitis (TAGU). The patient was initially managed with intraocular steroids and systemic steroids with minimal improvement of symptoms. The patient later required steroid sparing therapy with a tumor factor inhibitor to achieve remission. There is a growing prevalence of tattooing among the general population and a low reported rate of tattooing complications. Granulomatous tattoo reaction with associated uveitis should be a consideration in patients with tattoos presenting with \"idiopathic\" uveitis.", "affiliations": "University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.", "authors": "Carvajal Bedoya\|Guiset\|G\|0000-0002-3152-7855;Caplan\|Liron\|L\|;Christopher\|Karen L\|KL\|;Reddy\|Amit K\|AK\|0000-0002-5097-823X;Ifantides\|Cristos\|C\|", "chemical_list": "D013256:Steroids; D000068879:Adalimumab", "country": "United States", "delete": false, "doi": "10.1177/2324709620975968", "fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n33238758\n10.1177/2324709620975968\n10.1177_2324709620975968\nCase Report\nTattoo Granulomas With Uveitis\nhttps://orcid.org/0000-0002-3152-7855Carvajal Bedoya Guiset MD1 Caplan Liron MD, PhD12 Christopher Karen L. MD1 https://orcid.org/0000-0002-5097-823XReddy Amit K. MD1 Ifantides Cristos MD13 1 University of Colorado, Denver, CO, USA\n2 Rocky Mountain Regional Veterans Affairs\nMedical Center, Denver, CO, USA\n3 Denver Health Medical Center, Denver, CO,\nUSA\nGuiset Carvajal Bedoya, MD, University of Colorado\nSchool of Medicine, Barbara Davis Building—Rheumatology, 1775 Aurora Ct, B115, Aurora, CO\n80045, USA. Email: [email protected]\n25 11 2020 \nJan-Dec 2020 \n8 232470962097596818 9 2020 26 10 2020 31 10 2020 © 2020 American Federation for Medical Research2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Bilateral intraocular inflammation and simultaneous development of tattoo granulomas has\nbeen described in several case reports. The pathophysiology of this process is poorly\nunderstood, and it has been hypothesized that it could be a similar mechanism to systemic\nsarcoidosis versus a delayed hypersensitivity response. Granulomatous tattoo reaction with\nassociated uveitis can manifest with or without evidence of systemic sarcoidosis, and it\nis usually responsive to immunosuppression and/or tattoo removal. We present a patient\nwith no prior diagnosis of sarcoidosis who developed bilateral panuveitis and tattoo\nchanges suggestive of tattoo granulomas with uveitis (TAGU). The patient was initially\nmanaged with intraocular steroids and systemic steroids with minimal improvement of\nsymptoms. The patient later required steroid sparing therapy with a tumor factor inhibitor\nto achieve remission. There is a growing prevalence of tattooing among the general\npopulation and a low reported rate of tattooing complications. Granulomatous tattoo\nreaction with associated uveitis should be a consideration in patients with tattoos\npresenting with “idiopathic” uveitis.\n\nuveitisgranulomatumor necrosis factor-αtattooingpanuveitisRocky Mountain Regional Veterans Affairs Medical Centercover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nSurveys across multiple countries revealed that the prevalence of tattoos in the general\npopulation is approximately 24%. While tattoos are common, adverse reactions after tattooing\nare fairly infrequent, though these incidents are likely to be underreported.1 Granulomatous tattoo reaction with associated uveitis represents one such rare\nadverse reaction. The overall prevalence of this complication is unknown. A recent review of\nthe medical literature reported only 39 patients over a period of 66 years (1952-2018)\nsuffered from granulomatous tattoo reaction with associated uveitis.2 We report the case of a young adult who developed a granulomatous reaction after the\napplication of a large tattoo.\n\nCase Report\nA 32-year-old Caucasian male presented to the Ophthalmology Service at the Rocky Mountain\nRegional Veterans Affairs Medical Center for evaluation of several months of bilateral eye\nredness and blurry vison. Review of systems was notable for simultaneous onset of diffuse\nerythema, tenderness, induration, and pruritus of a large black ink tattoo over the right\narm and chest (Figure 1). This\ntattoo was inked 1 year prior to presentation. He had 2 other tattoos completed 10 years\nbefore, which were unaffected (Figure\n2).\n\nFigure 1. (A) Inflammation and induration of a large black ink tattoo over right arm and chest;\ntattoo was inked 1 year prior to presentation. (B) Resolution of inflammation after\nsystemic steroid use.\n\nFigure 2. (A/B) Unaffected tattoos performed 10 years prior to presentation.\n\nAt the time of initial presentation, ophthalmological examination with slit lamp revealed\nanterior chamber inflammation and iris synechiae. On optical coherence tomography, there was\nevidence of macular edema (Figure\n3). Skin examination was significant for inflammation, induration, and scant\ndesquamation in a pattern that closely matched the borders of the tattoo. Lungs were clear\nto auscultation. The rest of the history and physical examination was unremarkable.\n\nFigure 3. (A) Slit lamp examination of the left eye revealing iris synechia (head arrow). (B)\nOptical coherence tomography of the left eye macula showing macular edema\n(asterisks).\n\nNo clinical or serological evidence for other uveitis-associated diseases was elicited,\nincluding infections, sarcoidosis, or spondylarthritis. Comprehensive metabolic panel,\ncomplete blood count, urinalysis, thyroid stimulating hormone, free T4, ferritin, creatine\nphosphokinase, and aldolase tests were within normal limits. Erythrocyte sedimentation rate\nwas 13 mm/h, and serum angiotensin-converting enzyme concentration was 86 U/L (14-82).\nC-reactive protein, HLA-B27, antinuclear antibody, antineutrophil cytoplasmic antibody\n(including cytoplasmic, perinuclear, and atypical ANCA), lysozyme, QuantiFERON, HIV,\nhepatitis B and C serologies, rheumatoid factor, anticyclic citrullinated peptide\nantibodies, and computed tomography of the chest were all within normal limits. Punch\nbiopsies of the affected skin were obtained. Histological examination revealed granulomatous\ninflammation with associated tattoo ink deposition consistent with foreign body-type\ngranulomatous reaction (Figure 4).\nMelan A immunostain highlighted scattered single junctional benign melanocytes with control\nsamples staining appropriately.\n\nFigure 4. Histology from punch biopsies of the affected skin (hematoxylin and eosin stain at ×4\n[A] and ×20 [B] power) showing evidence of granulomatous inflammation (arrows) with\nassociated tattoo ink deposition (asterisks) consistent with foreign body-type\ngranulomatous reaction.\n\nThe patient was initially treated with topical ocular glucocorticoids without significant\nimprovement. He then required oral methylprednisolone 24 mg daily, tapered to 4 mg daily\nover 6 days. This agent led to rapid resolution of the inflammatory tattoo changes, but not\nof the macular and optic disc edema. A sub-tenon’s triamcinolone injection to both eyes\nresolved his ocular manifestation; however, tapering of his systemic glucocorticoids caused\nhis tattoo manifestations to reappear. Adalimumab at 40 mg subcutaneously every other week\nsatisfactorily terminated all of his symptoms. Unfortunately, after 3 months of therapy,\npatient developed an injection site reaction. Certolizumab 200 mg SQ every 2 weeks was\ninstituted. A follow-up examination 4 months later revealed minimal, if any, subtle\ninflammation in both eyes, mild worsening of the macular edema in his left eye, and visual\nacuity of 20/20 by Snellen chart.\n\nDiscussion\nTattoo granulomas with uveitis is an exclusion diagnosis. Sarcoidosis should always be\nruled out, even after histologic diagnosis. The histopathological diagnosis of sarcoidosis\nis challenging and drawing a definitive conclusion between sarcoidosis and foreign body\nreaction is not always possible. Granulomatous tattoo reaction with associated uveitis\nphysiopathology is not well understood, but multiple hypotheses have been suggested. A\ndelayed hypersensitivity reaction to ink given its toxic, mutagenic, and carcinogenic\ncompounds has been proposed.3 This large antigenic load may trigger this condition in susceptible individuals.1 A second hypothesis proposes a chronic mild antigenic stimulation from the tattoo ink\nleading to systemic granulomatous reaction consistent with sarcoidosis in susceptible individuals.4\n\nGenerally, all patients with TAGU undergo investigation for sarcoidosis. Patients found to\nhave underlying sarcoidosis usually do not have pulmonary involvement, raising the question\nas to whether this represents a different subset of sarcoidosis with a specific\nenvironmental antigen exposure. Patients with TAGU occurring without concurrent sarcoidosis\nare usually younger, and more likely to have black ink used for tattooing. Uveitis occurs\nalmost simultaneously with tattoo reaction, and symptoms present within the first year after tattooing.2 TAGU is usually responsive to immunosuppression or tattoo removal.5\n\nThis case resembles previous reports in that the patient presented with bilateral uveitis\nwith simultaneous cutaneous and ocular manifestations. Also, his tattoo reaction occurred\nafter using black ink. To the best of our knowledge, this is only the second reported case\nin which adalimumab was demonstrated to be resolve the patient’s signs and symptoms. Our\npatient also presented with panuveitis, which differs from previous reports in which\nanterior uveitis prevails.\n\nConclusion\nGranulomatous tattoo reaction with associated uveitis is a rare clinical entity and likely\nto be underdiagnosed. It should be a consideration in all patients presenting with uveitis\nof undetermined cause. Patients should be screened for tattoos, and if present, the tattoos\nshould be examined. Also, patients with tattoo changes must be actively asked for ocular\nsymptoms. With the increasing popularity of art tattooing or permanent makeup tattooing,\nmore cases of TAGU would be expected.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research,\nauthorship, and/or publication of this article: This work was supported in part by the\nRocky Mountain Regional Veterans Affairs Medical Center. The sponsor was not involved in\nthe design and conduct of the study; collection, management, analysis, and interpretation\nof data; preparation, review, or approval of the manuscript; and the decision to submit\nthe manuscript for publication.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case\nseries.\n\nInformed Consent: Written informed consent was obtained from the patient(s) for their anonymized\ninformation to be published in this article.\n\nORCID iDs: Guiset Carvajal Bedoya \nhttps://orcid.org/0000-0002-3152-7855\n\nAmit K. Reddy \nhttps://orcid.org/0000-0002-5097-823X\n==== Refs\nReferences\n1 \nWenzel S Rittmann I Landthaler M Bäumler W. \nAdverse reactions after tattooing: review of the literature and comparison\nto results of a survey\n. Dermatology .\n2013 ;226 :138 -147\n.23689478 \n2 \nKluger N. \nTattoo-associated uveitis with or without systemic sarcoidosis: a\ncomparative review of the literature\n. J Eur Acad Dermatol\nVenereol .\n2018 ;32 :1852 -1861\n.29763518 \n3 \nRorsman H Brehmer-Andersson E Dahlquist I , et al\nTattoo granuloma and\nuveitis\n. Lancet .\n1969 ;2 :27 -28\n.4182795 \n4 \nSepehri M Hutton Carlsen K Serup J. \nPapulo-nodular reactions in black tattoos as markers of sarcoidosis; study\nof 92 tattoo reactions from a hospital material\n.\nDermatology .\n2016 ;232 :679 -686\n.28166524 \n5 \nOstheimer TA Burkholder BM Leung TG Butler NJ Dunn JP Thorne JE. \nTattoo-associated uveitis\n. Am J\nOphthalmol . 2014 ;158 :637-643.e1.\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2324-7096", "issue": "8()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "granuloma; panuveitis; tattooing; tumor necrosis factor-α; uveitis", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D001706:Biopsy; D005549:Foreign-Body Reaction; D015745:Granuloma, Foreign-Body; D006801:Humans; D008269:Macular Edema; D008297:Male; D013256:Steroids; D013653:Tattooing; D014605:Uveitis; D014792:Visual Acuity", "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709620975968", "pmc": null, "pmid": "33238758", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "28166524;29763518;4182795;24875002;23689478", "title": "Tattoo Granulomas With Uveitis.", "title_normalized": "tattoo granulomas with uveitis" }	[ { "companynumb": "US-UCBSA-2020054739", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TAPERED TO 4 MG DAILY OVER 6 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CERTOLIZUMAB PEGOL" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "UVEITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CERTOLIZUMAB PEGOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "24 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "24", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CERTOLIZUMAB PEGOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": 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TATTOO GRANULOMAS WITH UVEITIS. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2020?8:1?4", "literaturereference_normalized": "tattoo granulomas with uveitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210513", "receivedate": "20210513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19254777, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-19652", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TRIAMCINOLONE" }, "drugadditional": null, "drugadministrationroute": 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{ "abstract": "Dabigatran is a direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation. The procedure to manage dabigatran-associated haemorrhages is not well formalized. Conventional haemodialysis has been evaluated with good results. Patients with dabigatran-associated bleeding may be unstable and convective techniques like venovenous haemodiafiltration (HDF) can be interesting. We report the case of a 74-year-old, critically ill patient with haemorrhagic shock and dabigatran overexposure due to acute kidney injury. He underwent HDF and dabigatran blood concentrations decreased from 325.3 ng/mL to 160.5 ng/mL. We report here key pharmacokinetics parameters (half-life, extraction coefficient, clearance).", "affiliations": "Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Pharmacology , University Hospital of Saint Etienne , Saint Priest en Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.", "authors": "Claisse\|Guillaume\|G\|;Delavenne\|Xavier\|X\|;Masson\|Ingrid\|I\|;Maillard\|Nicolas\|N\|;Alamartine\|Eric\|E\|;Mariat\|Christophe\|C\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ckj/sfv001", "fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 2581517710.1093/ckj/sfv001sfv001ContentsHaemodiafiltrationVenovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit Claisse Guillaume 1Delavenne Xavier 2Masson Ingrid 1Maillard Nicolas 1Alamartine Eric 1Mariat Christophe 11 Department of Nephrology, University Hospital of Saint Etienne, Saint Priest En Jarez, France2 Department of Pharmacology, University Hospital of Saint Etienne, Saint Priest en Jarez, FranceCorrespondence to: Guillaume Claisse; E-mail: [email protected] 2015 24 1 2015 24 1 2015 8 2 199 201 22 7 2014 2 1 2015 © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] is a direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation. The procedure to manage dabigatran-associated haemorrhages is not well formalized. Conventional haemodialysis has been evaluated with good results. Patients with dabigatran-associated bleeding may be unstable and convective techniques like venovenous haemodiafiltration (HDF) can be interesting. We report the case of a 74-year-old, critically ill patient with haemorrhagic shock and dabigatran overexposure due to acute kidney injury. He underwent HDF and dabigatran blood concentrations decreased from 325.3 ng/mL to 160.5 ng/mL. We report here key pharmacokinetics parameters (half-life, extraction coefficient, clearance).\n\ndabigatran overexposurehaemodiafiltrationhaemorrhagic shockintensive care\n==== Body\nContext\nDabigatran is a direct thrombin inhibitor indicated in prevention of thromboembolic disease in patients with non-valvular atrial fibrillation [1]. Contrary to vitamin K antagonists, no specific blood monitoring is recommended for dabigatran even if there is a real risk of accumulation in the case of renal impairment [2–4]. Importantly, there is no specific antidote of dabigatran. Presently, the procedure to reverse dabigatran in the case of life-threatening bleeding or in situations where urgent surgery is required is not well formalized. It is suggested to use procoagulant drugs [5, 6]. Additionally, based on the characteristics of dabigatran (small molecular weight of 630 Da and low binding to proteins, 30%), haemodialysis is proposed [7].\n\nPrevious studies have focused on removal of dabigatran using conventional haemodialysis, with good results [7–16]. Conventional dialysis usually means a diffusive method with high blood flow (∼350 mL/min), arteriovenous fistula and high dialysate rate (∼500 mL/min). Not rarely, patients with life-threatening bleeding need to be hospitalized in the intensive care unit (ICU) where conventional techniques are not always available. Furthermore, patients with massive bleeding can be haemodynamically unstable and conventional haemodialysis in this context may not be well tolerated. For these reasons, the use of convective-based renal replacement therapy (RRT) like haemodiafiltration (HDF) may have a place in the management of patients with undesirable blood concentration of dabigatran. However, very few data exist on the ability of those techniques to efficiently remove dabigatran from blood [17].\n\nWe report here the case of a patient admitted to the ICU for life-threatening bleeding in the context of dabigatran overexposure managed by HDF.\n\nCase report\nA 74-year-old man was presented to the emergency department with epigastric pain, asthaenia and drowsiness. He had a past medical history of chronic heart failure, chronic subdural haematoma, atrial fibrillation and chronic kidney disease stage 3b and received dabigatran 75 mg twice daily. He took his last dose of dabigatran 7 h before the admission. He was somnolent but arousable, confused with Glasgow Coma Scale 14, haemodynamically unstable with hypotension (95/51 mmHg), mottled skin and tachycardia (100 bpm). Mucocutaneous pallor was noted but without external bleeding. First biology results found anaemia with haemoglobin 7 g/dL (versus 11.5 g/dL two weeks before) and creatinine 276 µmol/L (versus 150 µmol/L usually) i.e. acute kidney injury stage 1 KDIGO. Plasma coagulation was abnormal with prothrombin ratio (PR) 28% and activated partial thromboplastin time (aPTT) 66 s. Blood dabigatran level was 534.9 ng/mL. Brain computed tomography found chronic subdural haematoma without acute bleeding. The patient received 3 packed red blood cells and 1000 mL of intravenous fluids (sodium chloride 0.9%). Upper gastrointestinal endoscopy was realized, finding stomach ulcer with acute bleeding. He was treated by local epinephrine injection and clipping with good efficiency. Continuous infusion by proton pump inhibitor was started (omeprazole 8 mg/h). He did not receive procoagulants drugs. The patient was hospitalized in ICU for RRT.\n\nIn ICU, a dialysis catheter (Blue FlexTip Catheter, 2 lumen, 16 cm, 12 Fr - ARROW®) was inserted in the right internal jugular vein. The patient was started on 4 h of HDF on PRISMA FLEX System (GAMBRO®) with a high-flux dialysis filter (Multiflow 60 AN69HF 0.60 m2 polyacrylonitrile hollow-fibre membrane). The blood (Qb), dialysate (Qd) and ultrafiltration (Quf) flow rates were 200 mL/min, 1 L/h and 3 L/h, respectively. Substitution fluids were delivered in predilution (1 L/h) and in postdilution (2 L/h) with zero net ultrafiltration. Dabigatran levels were sampled every 20 min in blood (inlet line) and effluent (ultrafiltration and dialysate volume collected every 20 min). Dabigatran level was measured by validated liquid chromatography tandem mass spectrometry method. The patient remained awake and alert for the entire session, without external bleeding. Diuresis was 250 mL on 8 h with residual clearance of creatinine measured at 14 mL/min. Dabigatran plasma concentration was 325.3 ng/mL at the beginning of RRT. It decreased gradually during the session to reach 160.5 ng/mL after 4 h (Figure 1). Decrease of dabigatran during HDF was of 25% at 2 h and 51% at 4 h. Conversely, the effluent level of dabigatran increased to reach 138.5 ng/mL at the end of the session. In parallel, aPTT decreased from 180 s at the initiation of HDF to 57.8 s 4 h after the session and PR increased from 30 to 41%. The patient did not receive any drugs that could have interfered with clotting time.\nFig. 1. Plasma and effluent dabigatran during HDF session. Black line represents dabigatran plasma concentrations; grey line represents dabigatran effluent concentration.\n\n\n\nMean haemodiafiltration clearance of dabigatran (Cl(hdf)) was 48 mL/min. Cl(hdf) was measured every 20 min using the recovery method according to the following equation Cl(hdf) = EV/P where E = effluent concentration of dabigatran, V = effluent rate and P = dabigatran plasma concentration. The half-life of dabigatran was 4.8 h. Only the terminal half-life was determined according to the following equation T1/2 = ln(2)/lambda(z) where lambda(z) is the slope of the terminal portion of the log transform concentrations versus time. This was obtained by unweighted linear regression of at least three concentrations.\n\nA rebound of concentrations of dabigatran was observed with a plasma level at 195.7 ng/mL 2 h after the end of the HDF session. Six hours after the HDF session, dabigatran concentration decreases to reach 11 ng/mL probably due to renal recovery. Because of renal recovery, clotting time improvement and decrease of dabigatran levels, no other dialysis session was realized.\n\nThe following day, haemoglobin was 8.6 g/dL. Control endoscopy was realized with a new clipping because of minimal bleeding. Renal function recovered with serum creatinine 168 µmol/L. Coagulation parameters continued to improve with PR 76% and aPTT 37 s at the patient's discharge. After cardiologic consultation, dabigatran was discontinued, replaced by aspirin because of a major risk of bleeding compared with the thromboembolic risk. The patient was discharged to home after 8 days.\n\nDiscussion\nThis case report focused on the interest of convective-based RRT in dabigatran-associated bleeding. In our report, dabigatran blood level decreased from 325.3 to 160.5 ng/mL with a 4-h session of HDF equivalent to a decrease of 51% of dabigatran. This correlated with clotting time improvement. Dabigatran half-life during HDF session was 4.8 h. This figure has to be compared with an expected half-life of 28 h in this patient with glomerular filtration rate (GFR) below 30 mL/min [8]. Thus, the half-life during HDF session is <25% of the half-life off therapy which by definition confirms that dabigatran is effectively removed by HDF [18].\n\nSeveral studies have previously reported the efficacy of haemodialysis techniques to clear dabigatran in different situations. Stangier et al. [8] found an extraction coefficient of dabigatran after 4 h of conventional haemodialysis at 68%, and Khadzhynov et al. [9] reported extractions ratios >45%. Other cases have been reported with comparable results [11–16]. More recently, Singh et al. [12] published on their experience of five cases of acute bleeding associated to dabigatran. All patients received conventional haemodialysis with a decrease of dabigatran ranging from 52 to 77%. In his study, an additional RRT session because of a rebound of dabigatran concentrations was performed using continuous venovenous haemodiafiltration (CVVHDF) apparently with a good result but very few data are given. Regarding the efficacy of convective techniques, Chiew et al. reported on a 66-year-old man treated by 32 h of CVVHDF for dabigatran overdose. They found a mean extraction ratio of 0.2% and a mean dabigatran clearance of 58.1 mL/min using the recovery method [17].\n\nThis case report is a prototype of a patient requiring intensive care, with acute bleeding due to dabigatran overdose. Importantly, we provide here full pharmacokinetic analyses allowing an evaluation of key pharmacokinetic parameters (clearance, half-life).\n\nOur work has other limitations. Decrease of dabigatran (51%) is less important than when conventional dialysis is used (50–80%), probably because of a low dialysate flow rate (1 L/h) and the small surface area of the filter (0.6 square metre). The absence of urine samples did not allow a direct evaluation of renal clearance of dabigatran but as the patient was oliguric we believed that renal excretion of dabigatran was negligible. The difference between dabigatran levels at the admission (534.9 ng/mL) and at the initiation of HDF (325.3 ng/mL) has probably more to do with haemodilution than renal excretion since the patient received three packed red blood cells and 1000 mL of saline solution before the beginning of HDF. The fact that the drug was not at steady-state when dialysis was started and the large distribution volume of dabigatran (70%) [7] can explain the relative increase of blood dabigatran concentrations during HDF session. Although thrombin time (TT) assay is the best test to assess dabigatran activity, it was not available in the emergency ward in our hospital. However, aPTT can be used for a qualitative assessment of dabigatran exposure, and some authors described a good correlation between aPTT and dabigatran concentrations [12].\n\nIn conclusion, this case report suggests that HDF may be an efficient approach for dabigatran removal and can be performed in the case of unstable, critically ill patients with dabigatran overexposure.\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 Connolly SJ Ezekowitz MD Yusuf S \nDabigatran versus warfarin in patients with atrial fibrillation . N Engl J Med \n2009 ; 361 : 1139 –1151 19717844 \n2 Stangier J \nClinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate . Clin Pharmacokinet \n2008 ; 47 : 285 –295 18399711 \n3 Stangier J Clemens A \nPharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor . Clin Appl Thromb Hemost \n2009 ; 15 (Suppl 1) : S9 –16 \n4 Liensenfeld K-H Lehr T Dansirikul C \nPopulation pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial . J Thromb Haemost \n2011 ; 9 : 2168 –2175 21972820 \n5 Ganetsky M Babu KM Salhanick SD \nDabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant . J Med Toxicol \n2011 ; 7 : 281 –287 21887485 \n6 Alikhan R Rayment R Keeling D \nThe acute management of haemorrhage, surgery and overdose in patients receiving dabigatran . Emerg Med J \n2014 ; 31 : 163 –168 . Epub 2013 Feb 22 23435652 \n7 McLellan AJ Schlaich MP \nDabigatran elimination: is haemodialysis effective? \nThromb Haemost \n2013 ; 109 : 580 –581 23389392 \n8 Stangier J Rathgen K Stähle H \nInfluence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study . Clin Pharmacokinet \n2010 ; 49 : 259 –268 20214409 \n9 Khadzhynov D Wagner F Formella S \nEffective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease . Thromb Haemost \n2013 ; 109 : 596 –605 23389759 \n10 Warkentin TE Margetts P Connolly SJ \nRecombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding . Blood \n2012 ; 119 : 2172 –2174 22383791 \n11 Chang DN Dager WE Chin AI \nRemoval of dabigatran by hemodialysis . Am J Kidney Dis \n2013 ; 61 : 487 –489 23219111 \n12 Singh T Maw TT Henry BL \nExtracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience . Clin J Am Soc Nephrol \n2013 ; 8 : 1533 –1539 . Epub 2013 May 23 23704302 \n13 Chen BC Sheth NR Dadzie KA \nHemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose . Am J Kidney Dis \n2013 ; 62 : 591 –594 23597859 \n14 Esnault P Gaillard PE Cotte J \nHaemodialysis before emergency surgery in a patient treated with dabigatran . Br J Anaesth \n2013 ; 11 : 776 –777 23650254 \n15 Wanek MR Horn ET Elapavaluru S \nSafe use of hemodialysis for dabigatran removal before cardiac surgery . Ann Pharmacother \n2012 ; 46 : e21 22872748 \n16 Bachellerie B Ruiz S Conil JM \nPatient with acute renal injury presenting dabigatran overdose: hemodialysis for surgery . Ann Fr Anesth Reanim \n2013 ; 33 : 44 –46 24378048 \n17 Chiew AL Khamoudes D Chan B \nUse of continuous veno-venous haemodiafiltration therapy in dabigatran overdose . Clin Toxicol (Phila) \n2014 ; 52 : 283 –287 24666338 \n18 Lavergne V Nolin TD Hoffman RS \nThe EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology . Clin Toxicol (Phila) \n2012 ; 50 : 403 –413 22578059\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2048-8505", "issue": "8(2)", "journal": "Clinical kidney journal", "keywords": "dabigatran overexposure; haemodiafiltration; haemorrhagic shock; intensive care", "medline_ta": "Clin Kidney J", "mesh_terms": null, "nlm_unique_id": "101579321", "other_id": null, "pages": "199-201", "pmc": null, "pmid": "25815177", "pubdate": "2015-04", "publication_types": "D016428:Journal Article", "references": "23435652;23219111;24378048;23389759;20214409;22578059;22383791;19717844;23650254;23704302;18399711;23389392;21887485;19696042;24666338;21972820;22872748;23597859", "title": "Venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit.", "title_normalized": "venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit" }	[ { "companynumb": "FR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-10423GD", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Shock haemorrhagic", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastric ulcer haemorrhage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CLAISSE G,DELAVENNE X,MASSON I,MAILLARD N,ALAMARTINE E,MARIAT C. VENOVENOUS HAEMODIAFILTRATION FOR THE MANAGEMENT OF DABIGATRAN OVERDOSE IN INTENSIVE CARE UNIT. CLIN KIDNEY J 2015 JAN 24;.", "literaturereference_normalized": "venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "FR", "receiptdate": "20150303", "receivedate": "20150303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10883591, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20150721" } ]
{ "abstract": "We report a case of a previously healthy woman in her early 70s who presented with 2 weeks of episodic abdominal pain and significant weight loss. Imaging of her abdomen revealed acute right ovarian torsion associated with bilateral ovarian enlargement and an indeterminant pelvic mass. An urgent laparoscopic bilateral oophorectomy was performed with pathological results consistent with triple-hit high-grade B-cell lymphoma. She was successfully treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, intrathecal methotrexate and venetoclax with complete remission after three cycles. Ovarian lymphoma is a rare entity and its genetic features have not been well described. We performed a literature review, describe the current knowledge regarding ovarian lymphoma and its therapeutic implication in the genomic age.", "affiliations": "Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA [email protected].;Department of Radiology, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.;Department of Pathology, Mount Auburn Hospital, Cambridge, Massachusetts, USA.;Department of Hematology and Oncology, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.", "authors": "Osataphan\|Soravis\|S\|;Augustynowicz\|Aleksandra\|A\|;Perrino\|Carmen\|C\|;Lam\|Prudence\|P\|", "chemical_list": "D000069283:Rituximab; D014750:Vincristine", "country": "England", "delete": false, "doi": "10.1136/bcr-2021-242423", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(5)", "journal": "BMJ case reports", "keywords": "gynaecological cancer; haematology (incl blood transfusion)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D010051:Ovarian Neoplasms; D000082843:Ovarian Torsion; D000069283:Rituximab; D014750:Vincristine", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "34059546", "pubdate": "2021-05-31", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Triple-hit high-grade B-cell lymphoma presenting with ovarian torsion.", "title_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion" }	[ { "companynumb": "US-FRESENIUS KABI-FK202106765", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN,UNKNOWN", 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"medicinalproduct": "ETOPOSIDE (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "SIX CYCLES ?DA?EPOCH?R", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIGH-GRADE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "SIX CYCLES ?DA?EPOCH?R", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIGH-GRADE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REPORTS. 2021 MAY?14(5):.", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210701", "receivedate": "20210701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19482784, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-302834", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", 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"drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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"activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "074290", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080352", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REPORTS. 2021?14(5):ARTICLE NUMBER E242423. DOI:10.1136/BCR?2021?242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20210629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19469637, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-SPO/USA/21/0136729", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", 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null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, 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"drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REP. 2021?14(5):UNK?UNK. DOI:10.1136/BCR?2021?242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20210629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19469946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-067545", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENETOCLAX" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIPITOR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "212299", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENETOCLAX" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INHALER", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL [SALBUTAMOL]" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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"drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN, S.. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motor neurone disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": 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TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION.. 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TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6?CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENETOCLAX" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, DAILY, DURING CYCLES 2, 3 AND 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REP. 2021?14:E242423 (1?7)", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210721", "receivedate": "20210721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19587993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-ACCORD-229808", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "042", 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"drugdosagetext": "600 MG DAILY FOR 5 DAYS DURING CYCLES 2, 3 AND 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "074513", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COLECALCIFEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM/GRANULOCYTE COLONY STIMULATING/LENOGRASTIM" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "074513", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIPITOR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENETOCLAX" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG DAILY FOR 5 DAYS DURING CYCLES 2, 3 AND 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REPORTS. 2021?14(5):ARTICLE NUMBER E242423. DOI:10.1136/BCR?2021?242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210702", "receivedate": "20210702", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19486433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Peritoneal dialysis treatment generates significant amounts of waste for disposal from patients' homes. In Australia, in the days after the onset of the COVID-19 pandemic, waste collection from homes was temporarily stopped. Our patient tried to dispose of his waste by burning the used bags and tubing, using paint thinner as an accelerant. We present a case report of the unusual neurological complication he developed.", "affiliations": "Department of Nephrology, 4435Launceston General Hospital, Tasmania, Australia.;Department of Nephrology, 4435Launceston General Hospital, Tasmania, Australia.;Department of Nephrology, 4435Launceston General Hospital, Tasmania, Australia.", "authors": "Dang\|Minh Huan\|MH\|0000-0001-5612-107X;Rodman\|Bodie\|B\|;Raj\|Rajesh\|R\|", "chemical_list": "D012997:Solvents; D014050:Toluene", "country": "United States", "delete": false, "doi": "10.1177/0896860820965025", "fulltext": null, "fulltext_license": null, "issn_linking": "0896-8608", "issue": "41(1)", "journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis", "keywords": "COVID-19; myoclonus; paint thinner; peritoneal dialysis", "medline_ta": "Perit Dial Int", "mesh_terms": "D001315:Australia; D000086382:COVID-19; D003140:Communicable Disease Control; D004781:Environmental Exposure; D005390:Fires; D006361:Heating; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D009207:Myoclonus; D010530:Peritoneal Dialysis; D012997:Solvents; D014050:Toluene", "nlm_unique_id": "8904033", "other_id": null, "pages": "101-103", "pmc": null, "pmid": "33499779", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Unexpected sequelae of the COVID-19 pandemic: A strange case of myoclonus in the Tasmanian winter.", "title_normalized": "unexpected sequelae of the covid 19 pandemic a strange case of myoclonus in the tasmanian winter" }	[ { "companynumb": "AU-BAXTER-2020BAX014829", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM CHLORIDE\\DEXTROSE\\MAGNESIUM CHLORIDE\\SODIUM CHLORIDE\\SODIUM LACTATE" }, "drugadditional": "3", "drugadministrationroute": "033", "drugauthorizationnumb": "017512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR PERITONEAL DIALYSIS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PERITONEAL DIALYSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIANEAL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Illness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Accidental exposure to product", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200715" } }, "primarysource": { "literaturereference": "DANG M, RODMAN B, RAJ R. UNEXPECTED SEQUELAE OF THE COVID?19 PANDEMIC: A STRANGE CASE OF MYOCLONUS IN THE TASMANIAN WINTER. PERITONEAL DIALYSIS INTERNATIONAL. 2021?41(1):101?103.", "literaturereference_normalized": "unexpected sequelae of the covid 19 pandemic a strange case of myoclonus in the tasmanian winter", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20210219", "receivedate": "20200724", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18068962, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]
{ "abstract": "The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies--infliximab (IFX), adalimumab (ADA) in Crohn's disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17--were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4-25) and 2.4 (95% CI 1.2 - 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1-2); p=0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.", "affiliations": "Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Computer Science and Statistics, Poznan University of Medical Sciences, Dabrowskiego Street 79, 60-529 Poznan, Poland.;Department of General Radiology, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.", "authors": "Eder\|Piotr\|P\|;Michalak\|Michal\|M\|;Katulska\|Katarzyna\|K\|;Lykowska-Szuber\|Liliana\|L\|;Krela-Kazmierczak\|Iwona\|I\|;Stawczyk-Eder\|Kamila\|K\|;Klimczak\|Katarzyna\|K\|;Szymczak\|Aleksandra\|A\|;Linke\|Krzysztof\|K\|", "chemical_list": "D000911:Antibodies, Monoclonal; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1038/srep10223", "fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group srep1022310.1038/srep10223ArticleMagnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn’s disease treated with anti-tumor necrosis factor antibodies Eder Piotr a1Michalak Michal 2Katulska Katarzyna 3Lykowska-Szuber Liliana 1Krela-Kazmierczak Iwona 1Stawczyk-Eder Kamila 1Klimczak Katarzyna 1Szymczak Aleksandra 1Linke Krzysztof 11 Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland2 Department of Computer Science and Statistics, Poznan University of Medical Sciences, Dabrowskiego Street 79, 60-529 Poznan, Poland3 Department of General Radiology, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Polanda [email protected] 05 2015 2015 5 1022304 12 2014 07 04 2015 Copyright © 2015, Macmillan Publishers Limited2015Macmillan Publishers LimitedThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies - infliximab (IFX), adalimumab (ADA) in Crohn’s disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17 - were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4 – 25) and 2.4 (95% CI 1.2 – 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1 – 2); p = 0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.\n==== Body\nThe introduction of anti-tumor necrosis factor alpha (anti-TNF) antibodies to the treatment of inflammatory bowel diseases (IBD) is considered to be one of the most important advances in gastroenterologic therapeutics in recent years. It has significantly improved the therapeutic possibilities especially in Crohn’s disease (CD) and changed the understanding of new treatment goals (mucosal healing, deep remission, steroid-free remission) in IBD1. However, there are still many questions as to when and how to treat patients with anti-TNFs. An important limitation of anti-TNF therapy is the loss of response to treatment over time2. In order to optimize the therapy and to improve its efficacy, individualization of therapeutic schedules has been proposed. The measurement of drug trough levels and anti-drug neutralizing antibodies allows for the modification of the treatment algorithms, which can lead to better long-term therapeutic outcomes, higher mucosal healing rates and less surgery3. Another possibility of treatment optimization is the appropriate selection of patients for anti-TNF therapy. Several predictors of a good response to anti-TNF agents or treatment failure have been described4. However, results from different studies concerning this aspect of the optimization of anti-TNF therapy are conflicting.\n\nThe development of new cross-sectional imaging techniques such as magnetic resonance enterography (MRE) has, in recent years, significantly improved the possibilities of assessing the activity of the small bowel in CD5. One of the most important advantages of MRE is that it enables the visualization of the whole spectrum of inflammatory lesions in CD – endoluminal, mural and extramural. Thus, MRE is helpful in describing CD phenotype and behavior according to the CD Montreal classification, which defines the disease location in the gastrointestinal tract and differentiates between luminal, penetrating, and stricturing forms of the disease6. Moreover, the non-invasive nature of MRE and the lack of radiation exposure allow for the repeated performance of this investigation, thereby enabling the dynamic assessment of CD progression or regression in time. This is particularly important in the monitoring of patients undergoing anti-TNF therapy.\n\nThe usefulness of MRE in CD diagnostics has been proved in many studies567. Moreover, there is an increasing number of scoring systems quantifying CD activity in MRE8910. It has been also shown, that MR imaging can be very helpful in monitoring anti-TNF therapy in CD patients111213. However, little is known whether MRE assessment can be helpful in predicting the response to anti-TNF therapy. In this study, we performed a retrospective analysis of the possible role of MRE in predicting long-term and steroid-free remission in patients with CD treated with biological agents, who initially responded to induction doses of anti-TNF antibodies. We also analyzed which MRE parameters can predict secondary non-response in this group of patients.\n\nResults\nAmong 90 patients treated with anti-TNF antibodies, 61 (68%) were primary responders (40 treated with IFX and 21 treated with ADA) and they comprised the final study group. All further analyses concerning the usefulness of different radiological, and biochemical parameters in predicting one-year efficacy of anti-TNF therapy corresponded to this group of patients.\n\nThere was a slight predominance in the number of female CD patients, mean disease duration was 6 ± 4 years. Biochemical analyses showed elevated inflammatory markers, like C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). Median CDAI was 267 points (95%CI: 232 – 292), which corresponded to a moderate clinical activity of CD. Almost 40% of patients underwent surgery in the past because of CD. The majority of patients demonstrated an inflammatory phenotype of CD. Full characteristics of the whole study group is presented in Table 1.\n\n44/61 (72%) patients reached the primary therapeutic end point, and 17/61 (28%) patients were classified as secondary non-responders. Secondary non-responders had significantly higher baseline CRP concentrations and higher platelet (PLT) counts when compared with patients who achieved steroid-free remission at week 52. Patients with longer disease duration and previous surgery were more probable to experience a secondary loss of response to anti-TNF therapy, however these differences were not statistically significant. In contrast to that, inflammatory phenotype of CD was significantly related to a higher probability of sustaining long-term remission at week 52 in comparison with penetrating and stricturing disease. Comparison between the two aforementioned study subgroups in terms of other biochemical, clinical, radiological and endoscopic features is presented in Table 2.\n\nCalculation of ROC curves showed that none of the MRE features, analyzed separately, had a potential to predict one-year remission in the study group. However, when two features, which are routinely assessed together in daily practice – bowel wall thickening and contrast enhancement - were also statistically analyzed together (range 0 – 4 points), ROC curve showed that they had the potential to predict the achievement of primary therapeutic end point in the study group (p = 0.01; AUC 0.67). An optimal cut-off point was ≥3 points, with 67% (CI 52 – 81%) sensitivity and 65% (CI 39 – 86%) specificity (Fig. 1). Combination analyses of other investigated features did not show any statistical significance.\n\nBinary logistic regression analyses revealed that bowel stenosis (p = 0.01) and the presence of intra-abdominal fistulas (p = 0.004) seen in MRE were significantly related to secondary non-response in the study group (Table 3). Other parameters were not related to a secondary treatment failure. In case of ulcerations the statistical analysis was impossible due to too few cases of ulcerations in the analyzed sample.\n\nFigures 2 and 3 show MRE images illustrating examples of response and non-response to one-year anti-TNF therapy.\n\nDiscussion\nClinical studies have shown that the initial response rate to anti-TNF therapy is approximately 60%. In this group, about 30% of patients maintained remission for up to one year214. Thus, appropriate qualification for biological therapy is essential in order to choose those patients who are the best candidates for anti-TNF treatment. Such patient selection is also important from a pharmacoeconomical point of view, and in order to minimize the risk of developing serious adverse reactions in subgroups of patients, who are already less likely to respond to anti-TNF therapy15.\n\nLittle is still known about which factors predict a good response or failure of anti-TNF therapy in CD. So far, several clinical, biochemical, and genetic parameters have been investigated in order to determine their association with response to anti-TNF agents. It has been hypothesized that the best candidate for anti-TNF therapy is a young, non-smoking patient with short CD duration, colonic disease location, non-stricturing CD behavior, having high CRP concentration and who had not been previously treated surgically4161718. Additionally it seems that the presence of perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and the absence of anti-Saccharomyces cerevisiae antibodies (ASCA) is associated with a failure of anti-TNF therapy19. The utility of several genetic factors in determining the expected efficacy of biologic agents is still questionable420. It should however be pointed out that the majority of the studies cited, referred to the usefulness of the various factors in predicting short-term response to anti-TNF therapy. Little is known about their usefulness in predicting long-term steroid-free remission of CD. We also do not know which factors could be associated with secondary loss of response to biological therapy\n\nAmong other investigations, MRE has in recent years become one of the most frequently used cross-sectional imaging methods in estimating CD behavior and activity5. Although it must be emphasized that, according to the consensus statement of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD), cross-sectional imaging methods (like MRE or ultrasound) have not been validated so far, current European Crohn’s and Colitis Organisation (ECCO) guidelines for imaging techniques in IBD indicate that they can be routinely applied for the assessment of the CD activity. It was also emphasized in the guidelines that MR techniques are especially useful as their diagnostic accuracy is similar to the accuracy of computed tomography, but with the major advantage of not imparting ionizing radiation2122. Thus, it seems to be essential to investigate the usefulness of MRE in predicting anti-TNF treatment efficacy. To the best of our knowledge, our study is one of the first of its type to determine the predictive role of several imaging features seen in MRE in patients with CD qualified for anti-TNF therapy.\n\nSeveral scores quantifying CD activity in MRE have been developed. The majority of them consist of similar MRE parameters, although none of those radiological features is pathognomonic for CD. Some of them can also be seen in other inflammatory small bowel disorders (mainly in gastrointestinal infectious diseases like yersiniosis), and non-inflammatory diseases, like for example small bowel neoplasms or ischemia23. That is why it is important to analyze all radiological features always in the clinical context. The most typical, major MRE features for CD are fat wrapping, an abnormal bowel wall thickness together with a mural hyperenhancement, enlargement and edema of mesenteric lymph nodes5. Another specific feature of CD – ulcerations, can be seen in the case of a full luminal distension, and it concerns only moderate to deep linear ulcers. Superficial, early ulcerations are not well demonstrated at MRE imaging.\n\nIn recent years, development of some new MRE sequences and methods for the assessment of CD activity has taken place. This increases the number of inflammatory parameters defined by MR imaging, among those discussed above. One of the most promising methods is the diffusion-weighted imaging (DWI). DWI reflects the changes in the water mobility caused by interactions with cell membranes, macromolecules, and alterations of the tissue environment24. It was shown that DWI enables detection of inflammatory activity in small bowel and colonic CD and is an accurate tool in assessing the disease activity. However, more studies are needed in this field.\n\nOne of the most well-known scores for “classical” MRE assessment in CD is the Magnetic Resonance Index of Activity (MaRIA) proposed by Rimola et al.8. MaRIA allows to assess the CD activity both in the small and the large bowel. This is due to the fact, that in the aforementioned study the colon was additionally filled with warm water by inserting a flexible rectal balloon catheter, which gave a sufficient large bowel distension810. This is in contrast with the majority of MRE protocols, in which MRE imaging is performed completely noninvasively, focusing on the assessment of the small bowel CD activity. Thus we decided to use a simple score allowing the assessment of CD activity in MRE performed according to a “standard” protocol10. In consequence, we also excluded from our study patients with isolated colonic CD location. The utility of the MRE score used in the current study was proved in an independent group of CD patients, and it correlated significantly with endoscopic activity, which was considered the gold standard for evaluation of CD activity. This score takes into account the most important and frequently assessed radiographic features of CD. Due to its simplicity, it can be easily applicable.\n\nThe statistical analysis revealed that an active inflammatory involvement of the intestine, reflected by bowel wall thickening and contrast enhancement in the baseline MRE were predictive of one-year steroid-free remission at week 52 in patients treated with anti-TNF agents. An optimal cut-off point was ≥3 points. This means that the best candidates for anti-TNF therapy are patients with bowel wall thickening ≥3 mm with a layered enhancement pattern after gadolinium administration or patients with bowel wall thickening >7 mm and any type of contrast enhancement. Additionally, the inflammatory (non-stenosing and non-penetrating) disease behavior was also significantly associated with long-term remission at week 52. These data confirm that high inflammatory burden of CD is associated with a good response to anti-TNF agents2526. However, it is still a matter of debate how to define this inflammatory burden in the case of CD. Nevertheless, patients with all active forms of CD can benefit from anti-TNF therapy, but probably those with high luminal inflammatory activity without complications will have better therapeutic outcomes. Our study is one of the first studies to show that this observation can also be applied to MRE investigations. However, it should be pointed out that only a combined approach including at least two features of MRE activity – presence of lesions with increased contrast enhancement - might indicate positive long-term therapeutic effects.\n\nDue to the increasing number of CD patients treated worldwide with anti-TNF antibodies, the problem of a secondary non-response becomes one of the most important limitations of this therapy2. Optimizing the treatment algorithm by increasing drug doses or by shortening the interval between doses, based on pharmacokinetic analyses, seems to be a valuable option in this clinical situation32728. However, the wide application of drug trough levels monitoring and anti-drug antibodies testing in everyday practice is still not commonly accessible3. Thus, more attention should be paid to the proper selection of patients who have the highest probability of achieving long-term CD remission with biological treatment. Our analysis showed that patients with at least one stenosis with prestenotic bowel dilatation assessed in dynamic sequences had an almost 6-fold higher risk of developing a secondary non-response when compared with patients without stenosis. What is more, even the presence of stenosis without prestenotic dilatation was significantly associated with secondary anti-TNF treatment failure. It should be emphasized that none of the patients with stenoses detected in MRE had radiographic signs of their fibrotic etiology. Additionally none of the patients suffered from obstructive gastrointestinal symptoms before starting the anti-TNF therapy. Current recommendations allow the use of anti-TNF agents in patients with stenotic CD, but only if they are not of a fibrotic origin2930. In fibrostenotic CD, endoscopic dilatation or surgical treatment should be considered31. Our study also shows the probability that patients with non-fibrotic stenoses should not be treated with anti-TNF agents, as they are at a high risk of developing a secondary non-response. Alternatively a more individualized and aggressive treatment algorithm should be introduced in this subgroup of patients, in order to avoid surgery.\n\nThe presence of intra-abdominal fistulas detected in MRE increased also the risk of developing secondary non-response to anti-TNF therapy. Current guidelines do not recommend pharmacological treatment in CD patients with intra-abdominal fistulas, as they should be treated surgically31. Unfortunately, this recommendation cannot always be easily applied in everyday clinical practice. Some patients do not accept surgical treatment, especially when they have undergone one or more bowel resections in the past. In our cohort of patients with intra-abdominal fistulas who initially responded to anti-TNF therapy and then developed secondary non-response (n = 6), all of them either did not initially accept the surgical treatment option or were disqualified from surgery because of other co-morbidities. After secondary failure of anti-TNF therapy, the majority of them (4/6) were treated surgically, and two received total parenteral nutrition (data not shown). Thus, since the efficacy of anti-TNF therapy in patients with intra-abdominal fistulas is poor, it seems that more attention should be paid in convincing patients to undergo surgical or alternative treatment.\n\nAnother observation from our study is that fat wrapping, which is believed to be one of the most characteristic features of an active CD, was not predictive for long-term therapeutic outcomes5. However, the grading score applied for this parameter could be less discriminative in order to differentiate active from inactive inflammatory lesions in MRE. That is why, as this parameter is always assessed together with vascular proliferation in the mesenteric fatty tissue, in order to make this aspect of CD activity estimation in MRE more discriminative, we summed up (scoring range 0–3 points) these two strictly interrelated parameters (fat wrapping and vascular proliferation in the mesenteric fatty tissue). In the first step, we performed an additional statistical analysis in which we divided our study group into three subgroups depending on their BMI results: <18.5 kg/m2 (n = 9), 18.5 – 25 kg/m2 (n = 45), and >25 kg/m2 (n = 7). Comparative analysis revealed no differences in the intensity of fat wrapping and vascular proliferation in those subgroups. Then, after checking that nutritional status does not interfere with the assessment of the discussed MRE parameters, we conducted further statistical analysis in order to estimate whether fat wrapping and vascular proliferation can be predictive for long-term treatment outcomes. The analysis, however, did not show their usefulness to predict the long-term response in our study group (OR for 2 points = 1; 95%CI 0.6 – 1.7, OR for 3 points = 1.3; 95% CI 0.04 – 37.1; p = 0.4). That is why we hypothesize that although this parameter is important for the assessment of CD activity, it seems probably not to have prognostic value.\n\nAnalysis of biochemical data also showed, that patients who were secondary non-responders had a significantly higher baseline CRP concentration. This seems to be in contrast with the results of some other studies. Louis et al. were first to show that a higher CRP level before treatment was associated with a positive clinical response to IFX25. Several other studies revealed that high baseline CRP concentration and its normalization after induction doses of anti-TNF agents were predictive of maintained clinical efficacy of biological therapy152632. On the other hand it has been shown that high CRP levels at the moment of diagnosis are associated with a worse CD course and that they predict the need for surgical treatment33. The most recent study by Magro et al. also showed that a high CRP concentration predicts rather a non-response to therapy with IFX in CD34. Thus, it should be emphasized that data in terms of the predictive role of CRP in anti-TNF therapy are conflicting. One can speculate, that the reason for these differences is probably due to differences in the etiology of CRP elevation. High inflammatory burden reflected by high CRP level is connected with a better outcome of anti-TNF therapy. The presence of CD complications (fistulas, stenoses) which can also lead to CRP elevation is related to a worse efficacy of biological agents. This hypothesis can also explain why patients with a higher baseline PLT count more frequently experienced a secondary non-response to anti-TNF therapy in our study group, as PLT are believed to be one of the most sensitive markers of CD severity35. However, it should be mentioned that although biochemical markers can be helpful, current guidelines emphasize the need of more complex assessment of CD activity by using endoscopy and cross-sectional imaging methods, which allow to estimate the whole spectrum of mucosal and transmural damage36.\n\nOur study has several limitations. The study group was strictly defined and the analyses concerned only primary responders to anti-TNF therapy, thus our data might be biased. Moreover, the number of patients is relatively low, which is due to very strict inclusion and exclusion criteria. This potentially could lead to some statistical misinterpretation of obtained data. Thus, although our study group is still one of the largest in the discussed subject matter, there is an urgent need to confirm the results in larger, prospective trials.\n\nBesides, it is still not fully clear which MRE features should be used in the first line in the assessment of CD activity, and how some of them should be interpreted. Some studies in that matter bring conflicting results. For example it is still being discussed how to define and stratify bowel wall thickening. Cutoff points for differentiation of different CD stages and its activity are still lacking or data are conflicting5. For example, there are some data using 4 mm as a cut off point for an abnormal bowel wall thickness37. It was also shown, that MRE was accurate for grading mural small bowel CD mainly in case of frank disease, and there could be some disease overstaging in the cases of patients in remission or mild CD activity538. Another unanswered question is whether bowel wall thickness requires an adjustment for different body weight or previous abdominal surgery. As there are no data in this field, we tried to analyze if these factors had an impact on CD mural lesions. We did not find any correlation between patients‘ BMI and bowel wall thickness. Moreover, we divided patients according to their BMI into three groups: <18.5 kg/m2 (n = 9), 18.5 – 25 kg/m2 (n = 45), and >25 kg/m2 (n = 7). Additional statistical analysis showed that bowel wall thickness was similar when compared patients with a different BMI. We also divided our study group into patients who underwent surgery in the past, and those without surgery. The median bowel wall thickness was 2 (95%CI 1.5–2.1) and 2 (95%CI 1.7–2) respectively, so the difference was not significant (p = 0.5). That is why we hypothesize that BMI or previous surgery do not influence this MRE parameter. Moreover, in the study performed by Gallego-Ojea et al. in which the usefulness of MRE in the detection of disease recurrence after surgery was shown, the authors also considered bowel wall thickness ≥3 mm as abnormal39. That is why, according to the current guidelines and teaching tutorials for radiologists, we decided to consider bowel wall thickness ≥3 mm as abnormal although some controversies in this field still exist40.\n\nAdditionally, heterogeneous enhancement of the bowel wall after contrast administration, believed to be a sign of active mural inflammation, was also suggested to be associated with fibrostenotic disease541. Moreover, in our study contrast enhancement was rated on a qualitative score. It is also unknown, whether characteristics of an individual patient can interefere with the reading of hyperenhancement in MRE. Although there are no data in this field, we divided our patients once again, depending on the BMI results, into three group, as presented above, and performed an additional statistical analysis. We did not find any association bewteen BMI and the character of contrast enhancement (data not shown). Thus, we hypothesize that this parameter is not related to patients‘ nutritional status.\n\nTo summarize this part of the discussion, we would like to emphasize that all selected MRE features assessed by the radiologist in our study are believed to be the most sensitive in detecting inflammatory activity of CD5678910. Despite some of the controversies presented above, MRE is still a method of choice in diagnosing and monitoring small bowel CD, and the majority of MRE assessment protocols used worldwide consist of very similar features as those assessed in our study.\n\nThe most important limitation of our study is that our MRE images were assessed by a single radiologist, thus, there was no interobserver agreement analysis performed. Moreover, a qualitative assessment of MRE images can be subjective, especially in the case of wall thickness and hyperenhancement quantitation. However, other studies have shown that the agreement between experienced radiologists in MR assessment is high, especially in large university radiological centers42. We would also like to emphasize that our radiologist is highly experienced in this type of MRE technique and was blinded to the anti-TNF efficacy results.\n\nIn summary it should be pointed out that MRE is an adequate tool not only in assessing CD extent and its activity. This cross-sectional imaging technique can also provide valuable prognostic data regarding the expected efficacy of anti-TNF treatment in a CD patient. Thus, it could be helpful in optimizing biological therapy. One of the main limitations of more frequent application of MRE is its relatively high cost. According to British data, the mean cost of MR enteroclysis is £268 and is slightly higher than MRE (£241). CT enterography seems to be the cheapest method, as its cost is £13343. Although costs can differ between countries and even between different departments, greater financial burden of MR imaging is a rule. Thus, some authors suggest that MRE should be performed only in the youngest patients and in other cases CT enterography is preferred. It seems, however, that a proper qualification for anti-TNF therapy can lead to the optimization of this expensive treatment and can lower its costs. Thus, as MRE is believed to be a useful method in the assessment of CD activity, the application of this method in qualification process for anti-TNF therapy could, hypothetically, be economically beneficial2223. The reason for this is that selecting the best candidates for anti-TNF treatment is still challenging, as approximately 30% of all CD patients will lose the initially obtained response to this therapy. Our study showed for one of the first times that MRE is probably useful in this selection process. This could limit toxicity, save costs and allow for the more accurate use of anti-TNF agents. However, in order to undoubtedly confirm these data, and to allow to directly translate them into clinical practice, there is a need for larger prospective trials in which an additional interobserver agreement analysis would be performed, before more widespread implementation of MRE in patients with CD will take place.\n\nMethods\nStudy population\nA retrospective cohort study was performed among patients with CD hospitalized between 2009 and 2012 at the Department of Gastroenterology, Human Nutrition and Internal Diseases at Poznan University of Medical Sciences. The inclusion criteria were as follows:\n\nage ≥18 years\n\nexacerbation of CD ineffectively treated with steroids and/or immunomodulators and meeting the eligibility criteria for anti-TNF therapy\n\nrealisation of MRE in accordance with the same protocol (presented below) 1–14 days before starting anti-TNF therapy\n\nresponse to the induction regimen of anti-TNF therapy with infliximab (IFX) or adalimumab (ADA) according to the criteria defined below, allowing for the continuation of maintenance therapy.\n\nThe exclusion criteria were:\n\nprimary non-response to anti-TNF therapy\n\nneed for any change in treatment regimen during induction doses of anti-TNF therapy\n\nisolated colonic location of CD, in which the diagnostic usefulness of MRE is lower than in ileal or ileocolonic CD\n\ntreatment with IFX or ADA within 52 weeks before enrollment into the study\n\npresence of any general contraindications to MR procedure, such as any metallic medical devices or foreign bodies (for example cardiac pacemaker, implanted cardioverter-defibrillator, joint replacement etc.) or renal insufficiency.\n\nThe clinical activity was routinely assessed by calculating the Crohn’s Disease Activity Index (CDAI)44. Each patient also underwent ileocolonoscopy performed by an experienced endoscopist (KL, IKK, LLS) with the estimation of the Simple Endoscopic Score for Crohn’s Disease (SES-CD)45. Biochemical markers of CD activity were measured routinely.\n\nMRE protocol\nMRE examinations were performed with a 1,5 Tesla clinical unit (Magnetom Avanto, Siemens Medical Solutions, Erlangen, Germany) with six-channel abdominal phased-array coils with a spine matrix coil. Each patient underwent MRE according to the same standard protocol previously described10. Namely, patients fasted for 6 hours before MRE. Patients were then given 1500 ml of oral polyethylene glycol (PEG) electrolyte solution (a single sachet of PEG diluted in 1500 ml of water – Fortrans, Ipsen Pharma) to drink 30–40 minutes before the investigation. Additionally, 40 mg of buscolysin (Hyoscini butylbromidum, Sopharma Plc, Bulgaria) was given intravenously prior to gadolinium administration in order to reduce bowel motility. To reduce respiratory movements and provide higher image quality, all imaging was performed under breath-hold conditions. The standard study protocol consisted of the sequences listed in Table 4.\n\nImage analysis\nThe most important and best studied MRE features of CD activity were assessed and quantified according to the scale proposed in Table 5678910. The usefulness of our score was proved in an independent cohort of CD patients, where it was compared with endoscopy, which is thought to be the gold standard in the assessment of CD activity10. The evaluation of MRE was performed by a single radiologist (KK), who was blinded to the efficacy results of anti-TNF therapy, and who has more than 10 years of experience in this imaging method.\n\nAnti-TNF treatment regimens and definition of therapeutic end points\nAccording to the anti-TNF induction regimen, patients were then given either 3 doses of 5 mg/kg body weight of IFX intravenously at week 0 – 2 – 6, or 160 mg of ADA subcutaneously at week 0, 80 mg at week 2 and 40 mg every other week until week 12.\n\nFollow-up investigations, including ileocolonoscopy, were performed at week 10 in case of IFX and at week 13 in case of ADA. Primary response to anti-TNF therapy was defined as a ≥100 – point decrease in the CDAI score (CDAI-100 response) with concomitant endoscopic improvement (any decrease in the SES-CD score). All primary responders were then placed on the maintenance regimen: 5 mg/kg body weight IFX every 8 weeks or 40 mg ADA every other week until week 52.\n\nThe therapeutic primary end point was clinical and steroid-free remission (CDAI < 150 points) at week 52. All patients who did not reach the therapeutic primary end point (CDAI ≥ 150 points and/or need for reintroducing steroids), and who needed optimization of anti-TNF therapy (increasing the doses or decreasing the intervals between doses) were considered as secondary non-responders. The main aim of the study was to assess which of the MRE parameters assessed during baseline imaging study have the potential to predict one-year steroid-free remission or secondary non-response in patients treated with anti-TNF antibodies.\n\nStatistical analysis\nDescriptive statistics was made by calculating means with standard deviations or medians with 95% confidence intervals. To compare clinical, endoscopic and biochemical data, the Student t test (parametric) was used when conditions of normality and equal variance were met. The Student t test was used with Welch correction when unequal variances were detected. When the normality test failed, a 2-tailed and exact Mann–Whitney rank sum test (nonparametric) was used. The differences in the disease behavior and disease locations in the study subgroups were assessed by using the Chi square test.\n\nEach MRE feature was graded according to the scoring system presented in Table 5 and assessed statistically separately, and – in the next step - in combination with other MRE features. In the second case the results were summarized. Receiver operating characteristic (ROC) curves were calculated to determine the potential of analyzed parameters to differentiate patients who had reached the therapeutic primary end point. An optimal cut-off point was calculated according to the highest accuracy (minimal false negative and false positive results). The area under the ROC curve (AUC) was used to check the prognostic value of particular parameters. For parameters which showed prognostic value, their sensitivity and specificity were additionally calculated.\n\nIn order to determine parameters which could be predictive of secondary loss of response to anti-TNF agents, a binary logistic regression analysis with subsequent cross validation was performed to identify the best discriminating MRE parameters by calculating the percentage overall correct classifications. For all studied parameters, odds ratios (OR) and 95% confidence intervals (CI) were presented.\n\nStatistical analyses were performed with MedCalc version 10.3.2 (MedCalc Software, Mariakerke, Belgium) and Statistica 10 (StatSoft Inc., Poland). All tests were considered significant at a p value of less than 0.05.\n\nThe study was approved by the Bioethics Committee at the Poznan University of Medical Sciences (No 774/13). An informed consent was obtained from all patients. The protocol of this study was performed strictly in accordance with the approved guidelines.\n\nAuthor Contributions\nP.E. designed the study, carried out the study and data analyses and drafted the manuscript. M.M. performed the statistical analyses and helped to draft the manuscript. L.L.S., K.K., I.K.K., K.S.E. helped to design and to revise the manuscript. K.K., A.S. and K.L. helped to revise and drafted the manuscript. All authors read and approved the final manuscript.\n\nAdditional Information\nHow to cite this article: Eder, P. et al. Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn’s disease treated with anti-tumor necrosis factor antibodies. Sci. Rep.\n5, 10233 doi: 10.1038/srep10223 (2015).\n\nWe would like to thank Clinton Muoto and Peter Jones for their perfect writing assistance (funding source for writing assistance: none).\n\nPE, LLS, and KK received lecture fees from Abbvie Poland. Other authors declare no competing financial interests.\n\nFigure 1 Receiver operator characteristic (ROC) curve showing that the score assessing bowel inflammatory thickening with contrast enhancement in the baseline magnetic resonance enterography (range 0 – 4 points) was predictive for long-term steroid-free remission at week 52 in Crohn’s disease patients treated with anti-TNF antibodies. An optimal cut-off point was ≥ 3, and it allowed to predict with 67% (confidence interval: 52 – 81%) sensitivity and 65% (confidence interval: 39 – 86%) specificity achievement of the primary therapeutic end point of the study (p = 0.01; area under the curve 0.67).\n\nFigure 2 Magnetic resonance enterography images illustrating an example of a response to one-year anti-tumor necrosis factor (anti-TNF) therapy in a patient with Crohn’s disease: (a) Week 0 - before anti-TNF therapy. T2-weighted sequence demonstrating thickening of a bowel wall (white arrows) without stenosis of the bowel lumen. (b) Week 0 - before anti-TNF therapy. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating thickening of a bowel wall with enhancing in the various layers of the wall - hyperintense signal corresponding to edema in acute inflammation (white arrows). (c) Week 52. T2-weighted sequence demonstrating decrease of thickening of the bowel wall (white arrows) after one-year anti-TNF therapy. (d) Week 52. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating decrease of thickening of the bowel wall with moderate enhancement typical for moderate activity of inflammation (white arrows) - after one-year anti-TNF therapy.\n\nFigure 3 Magnetic resonance enterography images illustrating an example of a non-response to one-year anti-tumor necrosis factor (anti-TNF) therapy in a patient with Crohn’s disease: (a) Week 0 - before anti-TNF therapy. T2-weighted sequence demonstrating thickening of a bowel wall (white arrows) with stenosis of the bowel lumen with prestenotic dilatation (asterisk). (b) Week 0 - before anti-TNF therapy. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating thickening of a bowel wall with enhancing in the various layers of the wall - hyperintense signal corresponding to edema in acute inflammation and dilatation of lumen (white arrows). (c) Week 52. T2-weighted sequence demonstrating increase of thickening of the bowel wall (white arrow) with stenosis of lumen and prestenotic dilatation (asterisk) after one-year anti-TNF therapy. (d) Week 52. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating increase of thickening of the bowel wall with enhancement typical for activity of inflammation (white arrows) – after one-year anti-TNF therapy.\n\nTable 1 Baseline characteristics of the 61 Crohn’s disease patients, who responded to the induction anti-tumor necrosis factor therapy (primary responders), which comprised the final study group.\nFeature\tn=61\t\nAge [mean ± SD]\t32 ± 10\t\nMale/female\t29/32\t\nDisease duration (years) [mean ± SD]\t6 ± 4\t\nC-reactive protein (mg/l) [mean ± SD]\t22.1 ± 26.1\t\nErythrocyte sedimentation rate (mm/h) [mean ± SD]\t32 ± 20\t\nRed blood cell count (106/mm3) [mean ± SD]\t4.4 ± 0.7\t\nHemoglobin (g/dl) [mean ± SD]\t12.3 ± 2.2\t\nHematocrit (%) [mean ± SD]\t37 ± 5\t\nWhite blood cell count (103/mm3) [mean ± SD]\t7.5 ± 3.7\t\nPlatelets (103/mm3) [mean ± SD]\t358 ± 109\t\nBody mass index (kg/m2) [mean ± SD]\t20.9 ± 3.3\t\nCrohn’s Disease Activity Index [median (95%CI)]\t267 (232 – 292)\t\nSimple Endoscopic Score for CD (SES-CD) [median (95%CI)]\t12 (11 – 18)\t\nIleal SES-CD [median (95%CI)]\t5 (4 – 7)\t\nColonic SES-CD [median (95%CI)]\t8 (7 – 13)\t\nPrevious surgery – n (%)\t24/61 (39%)\t\nDisease location – n (%)\t \t\nL1 (ileal)\t26/61 (43%)\t\nL3 (ileocolonic)\t35/61 (57%)\t\nDisease behavior – n (%)\t \t\nB1 (inflammatory)\t32/61 (53%)\t\nB2 (stricturing)\t10/61 (16%)\t\nB3 (penetrating)\t19/61 (31%)\t\nMedications\t \t\nSteroids\t26/61 (42%)\t\nAzathioprine\t53/61 (87%)\t\nAminosalicylates\t60/61 (98%)\t\nProbiotics\t46/61 (75%)\t\nAntibiotics\t15/61 (24%)\t\nPrevious anti-TNF therapy\t8/61 (13%)\t\nData are presented as means with standard deviations (SD) or medians with 95% confidence intervals (CI).\n\nTable 2 Comparison of baseline data (week 0) of Crohn’s disease patients who achieved one-year steroid-free remission at week 52 (responders) with secondary non-responders group.\nFeature\tResponders\tNon-responders\tp\t\nNumber of patients (%)\tn=44/61 (72%)\tn=17/61 (28%)\t \t\nAge (years) [mean ± SD]\t30 ± 8\t37 ± 13\tns\t\nMale/female –n (%)\t22/22\t7/10\t \t\nDisease duration (years) [mean ± SD]\t5 ± 3\t6 ± 5\tns\t\nC-reactive protein (mg/l) [mean ± SD]\t16.4 ± 15.7\t35.3 ± 38.7\t0.01\t\nErythrocyte sedimentation rate (mm/h) [mean ± SD]\t30 ± 18\t37 ± 23\tns\t\nRed blood cell count (106/mm3) [mean ± SD]\t4.4 ± 0.8\t4.4 ± 0.7\tns\t\nHemoglobin (g/dl) [mean ± SD]\t12.5 ± 2.1\t11.6 ± 2.5\tns\t\nHematocrit (%) [mean ± SD]\t38 ± 5\t36 ± 6\tns\t\nWhite blood cell count (103/mm3) [mean ± SD]\t7.3 ± 3.5\t7.9 ± 4.2\tns\t\nPlatelets (103/mm3) [mean ± SD]\t328 ± 98\t429 ± 103\t0.009\t\nBody mass index (kg/m2) [mean ± SD]\t21.2 ± 3\t20.9 ± 3.3\tns\t\nCrohn’s Disease Activity Index [median (95%CI)]\t264 (220 – 294)\t304 (216 – 331)\tns\t\nSimple Endoscopic Score for CD (SES-CD) [median (95%CI)]\t12 (11 – 18)\t12 (4 – 25)\tns\t\nIleal SES-CD [median (95%CI)]\t6 (4 – 7)\t6 (3 – 6)\tns\t\nColonic SES-CD [median (95%CI)]\t9 (6 – 12)\t12 (11 – 18)\tns\t\nDisease location – n (%)\t \t \t \t\nL1 (ileal)\t18/44 (41%)\t9/17 (53%)\tns\t\nL3 (ileocolonic)\t26/44 (59%)\t8/17 (47%)\tns\t\nDisease behavior – n (%)\t \t \t \t\nB1 (inflammatory)\t27/44 (61%)\t5/17 (29%)\t0.04\t\nB2 (stricturing)\t6/44 (14%)\t4/17 (24%)\tns\t\nB3 (penetrating)\t11/44 (25%)\t8/17 (47%)\tns\t\nPrevious surgery – n (%)\t15/44 (34%)\t9/17 (53%)\tns\t\nMedications\t \t \t \t\nSteroids\t21/44 (48%)\t5/17 (29%)\tns\t\nAzathioprine\t39/44 (87%)\t14/17 (82%)\tns\t\nAminosalicylates\t43/44 (98%)\t17/17 (100%)\tns\t\nProbiotics\t33/44 (75%)\t13/17 (76%)\tns\t\nAntibiotics\t8/44 (18%)\t7/17 (41%)\tns\t\nPrevious anti-TNF therapy\t5/44 (11%)\t3/17 (18%)\tns\t\nData are presented as means with standard deviations (SD) or medians with 95% confidence intervals (CI).\n\nTable 3 Binary logistic regression analysis showing which features of Crohn’s disease activity assessed in magnetic resonance enterography at week 0 were associated with a secondary non-response in patients treated with anti-TNF antibodies. Data are presented as odds ratios (OR) with 95% confidence intervals (CI).\nFeature\tStatistical significance in predicting secondary non-response to anti-TNF therapy\tThe percentage overall correct classifications\t\nBowel wall thickening\t1 point: OR 0.6; 95% CI (0.2 – 1.7); ns\t—\t\n \t2 points: OR 0.1; 95% CI (0.001 – 10); ns\t \t\nContrast enhancement\t1 point: OR 1.1; 95% CI (0.4 – 25); ns\t—\t\n \t2 points: OR 1.1; 95% CI (0.04 – 33.3); ns\t \t\nFat wrapping\tOR 0.9; 95% CI (0.3 – 2.5); ns\t—\t\nProliferation of mesenteric vasculature\t1 point: OR 1.2; 95% CI (0.6 – 2.5); ns\t—\t\n \t2 points: OR 1.6; 95% CI (0.1 – 25); ns\t \t\nLymphadenopathy\t1 point: OR 1.1; 95% CI (0.5 – 2); ns\t—\t\n \t2 points: OR 1.2; 95% CI (0.07 – 20); ns\t \t\nBowel wall ulcerations\tAnalysis impossible due to too few cases of ulcerations (4 cases, all in the long-term responders group) in analyzed sample\t—\t\nStenosis\t1 point: OR 2.4; 95% CI (1.2 - 5); p = 0.01\t75.40%\t\n \t2 points: OR 5.8; 95% CI (1.4 – 25); p = 0.01\t \t\nIntra-abdominal fistulas\tOR 1.4; 95% CI (1.1 – 2); p = 0.004\t75,5%\t\nDisease extent\t1 point: OR 0.6; 95% CI (0.3 – 1.25); ns\t—\t\n \t2 points: OR 0.4; 95% CI (0.08 – 1.6); ns\t \t\nTable 4 Sequences used in the magnetic resonance enterography protocol.\n \tRepetition time/echo time (ms)\tFlip angle\tSlice thickness (mm)\tIn plane resolution (mm)\tDistance factor (Axial) (mm)\tDistance factor (Coronal)(mm)\t\nTrue Fast Imaging with Steady-state free Precession (FISP)\t4/1,72\t60°\t4,0\t2,0 × 1,5\t0\t0,4\t\nSingle shot turbo spin echo sequence with fat suppression (HASTE)\t1100/116\t150°\t6,0\t1,5 × 1,6\t—\t1,8\t\nRetro Steady State Free Precession\t42,6/1,2\t73°\t6,0\t1,5 × 2\t—\t6,0\t\nFat-suppressed 3D T1-weighted Volumetric Interpolated Breath-Hold Examination (VIBE) before and three times - 30, 90 seconds and 5 minutes after intravenous injection of gadolinium contrast (Gadovist 1.0, Bayer Pharma AG, Germany, dose of 0.1 mmol/kg body weight followed by 20 ml of saline)\t6,10/2,74\t10°\t1,75\t2 × 2\t0,6\t0,6\t\nTable 5 Quantifying score of magnetic resonance enterographic features of Crohn’s disease activity 10.\nMRE feature\tGrading scale\t\nBowel wall thickening\t<3 mm: 0 pts\t3 – 7 mm: 1 pt\t>7 mm: 2 pts\t\nContrast enhancement1\tNone: 0 pts\tHomogenous pattern: 1 pt\tLayered pattern: 2 pts\t\nFat wrapping\tNone: 0 pts\tPresent: 1 pt\t\nProliferation of mesenteric vasculature\tNone: 0 pts\t<5 vessels/3 cm2 of mesenteric fat: 1 pt\t≥ 5 vessels/3 cm2 of mesenteric fat: 2 pts\t\nMesenteric lymphadenopathy\tNone: 0 pts\t<10 enlarged (diameter > 5 mm) lymph nodes: 1 pt\t≥ 10 enlarged (diameter > 5 mm) lymph nodes: 2 pts\t\nBowel wall ulcerations\tNone: 0 pts\tAt least one ulceration present, not exceeding ½ of bowel thickness: 1 pt\tAt least one ulceration present, exceeding ½ of bowel thickness: 2 pts\t\nStenotic complications2\tNone: 0 pts\tStenosis without prestenotic dilatation: 1 pt\tAt least one stenosis with prestenotic dilatation: 2 pts\t\nIntra-abdominal fistulas\tNone: 0 pts\tAt least one intra-abdominal fistula tract visible: 2 pts\t\nExtent of the disease in jejunum or ileum\t<1500 mm: 1 pt\t \t>1500 mm: 2 pts\t\n1assessed in comparison with the adjacent bowel loops.\n\n2decrease in bowel caliber in comparison with the adjacent bowel loops, with dilatation of the proximal segment and/or a collapse of the distal segment.\n==== Refs\nFeagan B. 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Radiol. \n16 , 597 –603 (2009 ).19282206 \nLouis E. \net al.\nA positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism . Scand. J. Gastroenterol. \n37 , 818 –824 (2002 ).12190096 \nJurgens M. \net al.\nLevels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn’s disease . Clin. Gastroenterol. Hepatol. \n5 , 421 –427 (2011 ).21334460 \nVelayos F. S. , Kahn J. G. , Sandborn W. J. & Feagan B. G. \nA test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab . Clin. Gastroenterol. Hepatol. \n6 , 654 –666 (2013 ).23357488 \nOrdas I. , Feagan B. G. & Sandborn W. J. \nTherapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease . Clin. Gastroenterol. Hepatol. \n10 , 1079 –1087 (2012 ).22813440 \nRieder F. , Zimmermann E. M. , Remzi F. H. & Sandborn W. J. \nCrohn’s disease complicated by strictures: a systematic review . Gut. \n7 , 1072 –1084 (2013 ).23626373 \nSorrentino D. \nRole of biologics and other therapies in stricturing Crohn’s disease: what have we learnt so far? \nDigestion \n1 , 38 –47 (2008 ).18285676 \nSampietro G. M. , Casiraghi S. & Foschi D. \nPerforating Crohn’s disease: conservative and surgical treatment . Dig. Dis. \n2 , 218 –221 (2013 ).24030229 \nKiss L. S. \net al.\nEarly clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn’s disease . Aliment. Pharmacol. Ther. \n8 , 911 –922 (2011 ).21883326 \nHenriksen M. \net al.\nC-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study . Gut. \n11 , 1518 –1523 (2008 ).18566104 \nMagro F. \net al.\nHigh C-reactive protein in Crohn’s disease patients predicts nonresponse to infliximab treatment . J. Crohns Colitis \n8 , 129 –136 (2014 ).23932786 \nCromer W. E. , Mathis J. M. , Granger D. N. , Chaitanya G. V. & Alexander J. S. \nRole of the endothelium in inflammatory bowel diseases . World J. Gastroenterol. \n5 , 578 –593 (2011 ).21350707 \nSandborn W. J. \net al.\nTreating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases . J. Crohns Colitis \n9 , 927 –935 (2014 ).24713173 \nKoh D. M. \net al.\nMR imaging evaluation of the activity of Crohn’s disease . Am. J. Roentgenol. \n177 , 1325 –1332 (2001 ).11717076 \nHorthuis K. , Bipat S. , Stokkers P. C. & Stoker J. \nMagnetic resonance imaging for evaluation of disease activity in Crohn’s disease: a systematic review . Eur. Radiol. \n19 , 1450 –1460 (2009 ).19189109 \nGallego Ojea J. C. , Echarri Piudo A. I & Porta Vila A. \nCrohn’s disease: the usefulness of MR enterography in the detection of recurrence after surgery . Radiologia . 53 , 552 –559 (2011 ).21450324 \nTolan D. J. \net al.\nMR enterographic manifestations of small bowel Crohn’s disease . RadioGraphics \n30 , 367 –384 (2010 ).20228323 \nPunwani S. \net al.\nMural inflammation in Crohn’s disease: location-matched histologic validation of MR imaging features . Radiology \n252 , 712 –720 (2009 ).19635832 \nSchleder S. \net al.\nInterobserver agreement in MR enterography for diagnostic assessment in patients with Crohn’s disease . Rofo. \n184 , 992 –997 (2013 ).23893750 \nBungay H. \nSmall bowel imaging in Crohn’s disease . Frontline Gastroenterol. \n3 , 39 –46 (2012 ).\nBest W. R. , Becktel J. M. , Singelton J. W. & Kern F. Jr.\nDevelopment of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study . Gastroenterology \n70 , 439 –444 (1976 ).1248701 \nDaperno M. \net al.\nDevelopment and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD . Gastrointest. Endosc. \n60 , 505 –12 (2004 ).15472670\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-2322", "issue": "5()", "journal": "Scientific reports", "keywords": null, "medline_ta": "Sci Rep", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D019540:Area Under Curve; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007082:Ileum; D000069285:Infliximab; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012189:Retrospective Studies; D016896:Treatment Outcome", "nlm_unique_id": "101563288", "other_id": null, "pages": "10223", "pmc": null, "pmid": "25993615", "pubdate": "2015-05-20", "publication_types": "D016428:Journal Article", "references": "11717076;12094865;12190096;1248701;12823146;15472670;17241859;18285676;18566104;19189109;19282206;19635832;19653291;20228323;21122530;21180547;21291629;21334460;21350707;21450324;21744431;21883326;22038857;22044414;22072290;22251435;22359399;22813440;22977028;23122965;23293739;23357488;23411006;23474779;23583097;23626373;23765176;23778300;23789658;23893750;23932786;24030229;24177375;24713173;28839630", "title": "Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies.", "title_normalized": "magnetic resonance enterographic predictors of one year outcome in ileal and ileocolonic crohn s disease treated with anti tumor necrosis factor antibodies" }	[ { "companynumb": "PL-JNJFOC-20150902776", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "AT WEEK 0-2-6, TILL WEEK 12", "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROBIOTICS NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROBIOTICS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fistula", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal stenosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EDER P, MICHALAK M, KATULSKA K, LYKOWSKA-SZUBER L, KRELA-KAZMIERCZAK I, STAWCZYK-EDER K, ET AL. MAGNETIC RESONANCE ENTEROGRAPHIC PREDICTORS OF ONE-YEAR OUTCOME IN ILEAL AND ILEOCOLONIC CROHN^S DISEASE TREATED WITH ANTI-TUMOR NECROSIS FACTOR ANTIBODIES. SCIENTIFIC REPORTS 2015;5.", "literaturereference_normalized": "magnetic resonance enterographic predictors of one year outcome in ileal and ileocolonic crohn s disease treated with anti tumor necrosis factor antibodies", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20150909", "receivedate": "20150909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11480415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "Drug-induced liver injury (DILI) is rare in children and adolescents, and, consequently, data are remarkably limited. We analyzed the causes, clinical and biochemical features, natural history, and outcomes of children with DILI. Consecutive children with DILI from 1997 to 2004 (retrospective) and 2005 to 2010 (prospective) were studied based on standard criteria for DILI. Thirty-nine children constituted 8.7% of 450 cases of DILI. There were 22 boys and 17 girls. Median age was 16 years (range, 2.6-17). Combination antituberculous drugs were the most common cause (n = 22), followed by the anticonvulsants, phenytoin (n = 10) and carbamazepine (n = 6). All of the 16 children (41%) who developed hypersensitivity features, such as skin rashes, fever, lymphadenopathy, and/or eosinophilia, including the 3 with Stevens-Johnson syndrome, survived. Those with hypersensitivity presented earlier (24.5 versus 35 days; P = 0.24) had less severe disease (MELD, 16 versus 29; P = 0.01) and had no mortality (0/16 versus 12/23; P < 0.001), compared to those without hypersensitivity. The 12 fatalities were largely the result of antituberculous DILI (n = 11). The presence of encephalopathy and ascites were associated with mortality, along with hyperbilirubinemia, high international normalized ratio, and serum creatinine. According to the Roussel Uclaf Causality Assessment Method, 18 were highly probable, 14 probable, and 7 possible. Thirty-two children were hospitalized.\n\n\nCONCLUSIONS\nDILI is not uncommon in children and accounts for 8.7% of all patients with DILI. Antituberculous drugs and anticonvulsants are the leading causes of DILI in India. Overall mortality is high (30.7%), largely accounted by antituberculous drugs. Children with DILI and hypersensitivity features present early, have less severe disease, and, consequently, a better prognosis, compared to those without, and are often associated with anticonvulsants or sulfonamides.", "affiliations": "Department of Gastroenterology, St. John's Medical College Hospital, Bangalore, India. [email protected]", "authors": "Devarbhavi\|Harshad\|H\|;Karanth\|Dheeraj\|D\|;Prasanna\|K S\|KS\|;Adarsh\|C K\|CK\|;Patil\|Mallikarjun\|M\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/hep.24527", "fulltext": null, "fulltext_license": null, "issn_linking": "0270-9139", "issue": "54(4)", "journal": "Hepatology (Baltimore, Md.)", "keywords": null, "medline_ta": "Hepatology", "mesh_terms": "D000293:Adolescent; D017677:Age Distribution; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D004342:Drug Hypersensitivity; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D015994:Incidence; D007194:India; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D018709:Statistics, Nonparametric; D015996:Survival Rate", "nlm_unique_id": "8302946", "other_id": null, "pages": "1344-50", "pmc": null, "pmid": "21735470", "pubdate": "2011-10", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Drug-Induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents.", "title_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents" }	[ { "companynumb": "IN-PFIZER INC-2015362026", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151109", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701224, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000663", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706427, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000662", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706616, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362035", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701216, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362032", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000664", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11715160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362033", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701225, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362030", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54:1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701241, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362027", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54:1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000660", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706431, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000661", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "BACKGROUND\nPoisoning is a worldwide public health problem that involves individuals of all ages and a wide range of chemicals. This study investigated the data from two health information systems to characterize poisoning events in the Federal District (DF), Brazil.\n\n\nMETHODS\nData related to the period from 2009 to 2013 were obtained from the poison information center (Centro de Informação Toxicológica, CIT) and the Notifiable Diseases Information System (Sistema Nacional de Agravos de Notificação, SINAN) of the DF.\n\n\nRESULTS\nA total of 3622 cases were reported to CIT-DF and 5702 cases to SINAN-DF. Most of the cases in CIT-DF (53%) occurred with children up to 9 years old, while this corresponded to 33.9% in SINAN-DF. Unintentional poisoning was the main circumstance involved in the cases. Pharmaceuticals were the main agent (44.3-47.1% of the cases), mainly clonazepan and paracetamol, and pesticides the most fatal (2.4% fatality rate). Out of the 47 fatal cases reported to the systems, only four were reported to both; six cases occurred with children up to 6 years.\n\n\nCONCLUSIONS\nUnder-reporting and missing information were identified in both systems, but the data were complementary to describe the epidemiology of poisoning cases in the DF.", "affiliations": "Poison Information Center of the Federal District, Heath Department of the Government of Federal District, Brasilia, DF, Brazil.;Laboratory of Toxicology, Department of Pharmaceutical Sciences, University of Brasilia, Brasilia, DF, Brazil.", "authors": "Magalhães\|Andrea Franco Amoras\|AFA\|;Caldas\|Eloisa Dutra\|ED\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/pubmed/fdy008", "fulltext": null, "fulltext_license": null, "issn_linking": "1741-3842", "issue": "41(1)", "journal": "Journal of public health (Oxford, England)", "keywords": "Brazil; Federal District; chumbinho; information systems; pesticides; pharmaceuticals; poisoning", "medline_ta": "J Public Health (Oxf)", "mesh_terms": "D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D003625:Data Collection; D005260:Female; D063005:Health Information Systems; D006801:Humans; D007223:Infant; D008297:Male; D019221:Mandatory Reporting; D008875:Middle Aged; D011039:Poison Control Centers; D011041:Poisoning; D011247:Pregnancy; D012189:Retrospective Studies; D035141:Voluntary Programs; D055815:Young Adult", "nlm_unique_id": "101188638", "other_id": null, "pages": "203-211", "pmc": null, "pmid": "29509912", "pubdate": "2019-03-01", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Two health information systems to characterize poisoning in Brazil-a descriptive study.", "title_normalized": "two health information systems to characterize poisoning in brazil a descriptive study" }	[ { "companynumb": "BR-PFIZER INC-2019164894", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "050670", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." } ], "patientagegroup": null, "patientonsetage": "1", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Accidental exposure to product", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MAGALHAES, A.. TWO HEALTH INFORMATION SYSTEMS TO CHARACTERIZE POISONING IN BRAZIL- A DESCRIPTIVE STUDY. JOURNAL OF PUBLIC HEALTH. 2019?41(1):203-211", "literaturereference_normalized": "two health information systems to characterize poisoning in brazil a descriptive study", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20190422", "receivedate": "20190422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16224210, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "BR-JNJFOC-20200715007", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product prescribing error", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAGALHAES A, CALDAS E. TWO HEALTH INFORMATION SYSTEMS TO CHARACTERIZE POISONING IN BRAZIL A DESCRIPTIVE STUDY. JOURNAL OF PUBLIC HEALTH. 2018 MAR 02?41 (1):203?211.", "literaturereference_normalized": "two health information systems to characterize poisoning in brazil a descriptive study", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20200716", "receivedate": "20200716", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18032850, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "We studied the outcome of 47 adult patients with relapsed acute leukaemia (AML = 25 and ALL = 22) treated with FLAG-mitoxantrone regimen. Median time to relapse was 10.7 months (range 1.9-27.7). Complete remission (CR2) was 60.1% which was significantly more frequent in ALL compared to AML (P = 0.049). WBC count < 100 × 109/L at initial diagnosis and time to relapse > 1 year were significantly predictor for CR2 in AML (P = 0.005 for both). Induction death was significantly higher in ALL compared to AML (P = 0.039). Median follow-up was 4.0 months (0.9-119.8) for AML and 2.1 months (range 0.6-118.1) for ALL. Nine patients underwent allogeneic stem-cell transplantation (allo-SCT). Estimated overall survival (OS) at 12 and 18 months was 60.5 and 34.6%, respectively, for AML, and 39.9 and 29.9%, respectively, for ALL. For AML patients failure to achieve CR, WBC count at initial diagnosis > 5 × 109/L and poor cytogenetic risk group was significant predictors of poor OS (P = 0.010, P = 0.025, and P = 0.015, respectively). For ALL patients failure to achieve of CR, WBC count at relapse < 5 × 109/L (CR patients) and lack of any type of consolidation therapy were significant predictor of poor OS (P < 0.001, P = 0.008, P = 0.008, respectively).", "affiliations": "Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. [email protected].;Mediclinic North Wing, Dubai, United Arab Emirates.;Department of Hematology, Oncology Tawam Hospital, Al Ain, United Arab Emirates.;Department of Hematology, Oncology Tawam Hospital, Al Ain, United Arab Emirates.", "authors": "Hassan\|Inaam Bashir\|IB\|;Kristensen\|Jorgen\|J\|;Al Qawasmeh\|Khalid\|K\|;Alam\|Arif\|A\|", "chemical_list": "D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D008942:Mitoxantrone; D014740:Vidarabine", "country": "Japan", "delete": false, "doi": "10.1007/s12185-018-2478-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "108(4)", "journal": "International journal of hematology", "keywords": "ALL; AML; FLAG–mitoxantrone; Re-induction; Relapse", "medline_ta": "Int J Hematol", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D018572:Disease-Free Survival; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D060828:Induction Chemotherapy; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D012008:Recurrence; D015996:Survival Rate; D014479:United Arab Emirates; D014740:Vidarabine", "nlm_unique_id": "9111627", "other_id": null, "pages": "390-401", "pmc": null, "pmid": "29951735", "pubdate": "2018-10", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "7528855;9815970;2045861;19806665;14675405;15856358;3276823;17611565;1737098;19543516;23407597;9722289;16832677;25922062;20872554;18076637;11475146;15632409;11806988;14671635;19880497;11574763;27587380;20714942;16988532;20385793;8374873;20003823;17032921;23468219;11167793;27207612;19008455;23243288;10738999;21131038;16105981;8418222;20010621;22511497", "title": "Re-induction chemotherapy using FLAG-mitoxantrone for adult patients with relapsed acute leukemia: a single-center experience from United Arab Emirates.", "title_normalized": "re induction chemotherapy using flag mitoxantrone for adult patients with relapsed acute leukemia a single center experience from united arab emirates" }	[ { "companynumb": "PHHY2018AE121284", "fulfillexpeditecriteria": "1", "occurcountry": "AE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G/M2, UNK(OVER 2 H, DAYS 1-5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK(1 H AT DAYS 1, 3, AND 5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "125553", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 UG, QD (FROM DAY 6 )", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/M2, UNK (OVER 30 MIN, DAYS 1-5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Recurrent cancer", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HASSAN IB, KRISTENSEN J, QAWASMEH KA, ALAM A. RE-INDUCTION CHEMOTHERAPY USING FLAG-MITOXANTRONE FOR ADULT PATIENTS WITH RELAPSED ACUTE LEUKEMIA: A SINGLE-CENTER EXPERIENCE FROM UNITED ARAB EMIRATES.. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2018?108(4):391-401", "literaturereference_normalized": "re induction chemotherapy using flag mitoxantrone for adult patients with relapsed acute leukemia a single center experience from united arab emirates", "qualification": "3", "reportercountry": "AE" }, "primarysourcecountry": "AE", "receiptdate": "20181012", "receivedate": "20181012", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15494593, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]
{ "abstract": "The purpose of this study was to evaluate the incidence of the administration of potentially inappropriate medications (PIMs) and the potential drug-drug interactions (pDDIs) in older patients in emergency departments (EDs) over a 12-month period and to identify the factors associated with the administration of PIMs.\nThis retrospective study was conducted using the electronic medical records from two university-affiliated teaching hospitals in South Korea. ED visit cases of patients aged 65 and older from January 1, 2013, to December 31, 2013, were included in the analysis. Among the medications administered in ED, PIMs or pDDIs were identiﬁed using a drug utilization review program available in Korea.\nDuring the study period, a total of 13,002 ED visit cases were reported from 10,686 patients. The proportion of ED visit cases with any PIM was 79.2% and the average number of PIMs was 2.7 (range, 1-17). The most commonly administered PIMs that were contraindicated or should have been used with caution were ketorolac (41.3%) and metoclopramide (10.3%), respectively. Multivariate regression analysis indicated that female patients (p = 0.012), patients with more than six drugs in the ED (p < 0.001), and visits longer than 300 minutes (p = 0.026) were significantly associated with PIM administration in the ED. Potential DDIs between the medications administered in EDs were observed in 20.5% of total visit cases, with ketorolac being the most frequently reported drug in contraindicated drug combinations.\nThis study demonstrated a high incidence of the administration of PIMs and medications with pDDIs in older patients in EDs and revealed the characteristics that are significantly associated with an increased risk of PIM administration. Healthcare providers in EDs should consider the risk of administering PIMs or medications with pDDIs, especially when treating older patients.", "affiliations": "College of Pharmacy, Korea University, Sejong, Republic of Korea.;Institute of Pharmaceutical Science, Korea University, Sejong, Republic of Korea.;Department of Pharmacy, Gang Neung Asan Hospital, Gangneung, Republic of Korea.;Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.;College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.;College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.", "authors": "Kim\|Kyungim\|K\|0000-0001-7997-696X;Jung\|Jinyoung\|J\|0000-0002-6038-6860;Kim\|Haesook\|H\|;Kim\|Jung Tae\|JT\|;Oh\|Jung Mi\|JM\|0000-0002-1836-1707;Kim\|Hyunah\|H\|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/TCRM.S291458", "fulltext": "\n==== Front\nTher Clin Risk Manag\nTher Clin Risk Manag\ntcrm\ntcriskman\nTherapeutics and Clinical Risk Management\n1176-6336 1178-203X Dove \n\n291458\n10.2147/TCRM.S291458\nOriginal Research\nPotentially Inappropriate Prescriptions to Older Patients in Emergency Departments in South Korea: A Retrospective Study\nKim et alKim et alhttp://orcid.org/0000-0001-7997-696XKim Kyungim 12* http://orcid.org/0000-0002-6038-6860Jung Jinyoung 2* Kim Haesook 3 Kim Jung Tae 4 http://orcid.org/0000-0002-1836-1707Oh Jung Mi 5 Kim Hyunah 67 1 College of Pharmacy, Korea University, Sejong, Republic of Korea\n2 Institute of Pharmaceutical Science, Korea University, Sejong, Republic of Korea\n3 Department of Pharmacy, Gang Neung Asan Hospital, Gangneung, Republic of Korea\n4 Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea\n5 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea\n6 College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea\n7 Drug Information Research Institute, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea\nCorrespondence: Hyunah Kim College of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul,04310, Republic of KoreaTel +82-2-2077-7961 Email [email protected]* These authors contributed equally to this work\n\n\n19 2 2021 \n2021 \n17 173 181\n10 11 2020 18 1 2021 © 2021 Kim et al.2021Kim et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nThe purpose of this study was to evaluate the incidence of the administration of potentially inappropriate medications (PIMs) and the potential drug–drug interactions (pDDIs) in older patients in emergency departments (EDs) over a 12-month period and to identify the factors associated with the administration of PIMs.\n\nPatients and Methods\nThis retrospective study was conducted using the electronic medical records from two university-affiliated teaching hospitals in South Korea. ED visit cases of patients aged 65 and older from January 1, 2013, to December 31, 2013, were included in the analysis. Among the medications administered in ED, PIMs or pDDIs were identiﬁed using a drug utilization review program available in Korea.\n\nResults\nDuring the study period, a total of 13,002 ED visit cases were reported from 10,686 patients. The proportion of ED visit cases with any PIM was 79.2% and the average number of PIMs was 2.7 (range, 1–17). The most commonly administered PIMs that were contraindicated or should have been used with caution were ketorolac (41.3%) and metoclopramide (10.3%), respectively. Multivariate regression analysis indicated that female patients (p = 0.012), patients with more than six drugs in the ED (p < 0.001), and visits longer than 300 minutes (p = 0.026) were significantly associated with PIM administration in the ED. Potential DDIs between the medications administered in EDs were observed in 20.5% of total visit cases, with ketorolac being the most frequently reported drug in contraindicated drug combinations.\n\nConclusion\nThis study demonstrated a high incidence of the administration of PIMs and medications with pDDIs in older patients in EDs and revealed the characteristics that are significantly associated with an increased risk of PIM administration. Healthcare providers in EDs should consider the risk of administering PIMs or medications with pDDIs, especially when treating older patients.\n\nKeywords\nemergency departmentolder adultspotentially inappropriate medicationsdrug–drug interactionsdrug utilization reviewNational Research Foundation, KoreaMinistry of Health & WelfareThis study was supported by the National Research Foundation, Korea (NRF-2020R1F1A1069257) and the Ministry of Health & Welfare (MOHW, Korea).\n==== Body\nIntroduction\nThe emergency department (ED), the place to institute the immediate medical care of patients with acute illness or injury, is at the intersection between inpatient and outpatient care and can have a meaningful impact on patients’ conditions.1–3 However, EDs are of increasing concern as high-risk environments for potentially inappropriate medication (PIM) use and adverse drug events. Certain characteristics of EDs such as patients overcrowding, a lack of skilled workers, and the high turnover of admitted or discharged patients can hinder the provision of optimal emergency care services.4,5\n\nAs the aging of society accelerates, the older adults aged 65 and over account for the largest and fastest growing age group of patients visiting EDs. The proportion of visits by older patients to EDs was reported as 24% in Italy, 31% in Spain, and 22% in the United States.6–8 In Korea, the rate of admission to EDs by older patients has risen from 15.2% in 2005 to 23.9% in 2016.9 Because older adults are sensitive to medicines, the administration of PIMs can lead to adverse drug events, which can have serious medical and safety consequences especially for older adults.10 Moreover, the side effects of these drugs can cause problems long after administration, as many drugs have a longer half-life in the older adults than in younger age people due to changes in pharmacokinetic parameters with aging.11 Some previous studies have shown that exposure to PIMs or potential drug–drug interactions (pDDIs) was associated with an increased risk of re-hospitalization and unplanned hospitalization in the older adults.12–14 Therefore, the need for and importance of appropriate medication use for the older adults visiting EDs should be particularly emphasized.\n\nPotentially inappropriate prescriptions have been well studied in both nursing home and community-dwelling older adult settings. However, less is known about it for older patients visiting EDs. Therefore, the purposes of this study were to determine the incidence and characteristics of PIM use and pDDIs and to identify the factors related to PIM administration, with a particular focus on the older patients visiting EDs.\n\nPatients and Methods\nStudy Population and Data Collection\nThis retrospective study was conducted from January to December 2013 at two university-affiliated teaching hospitals in South Korea. Of the patients who visited the EDs in 2013, those aged 65 years and older were included in this study. Patient demographic information and visit characteristics to the EDs were collected from each hospital’s electronic medical records (EMRs). These included the patient’s age, sex, diagnosis in the ED (ICD-10 code), the medications administered in the ED (brand name, ingredient, ATC code), their length of ED stay, and condition after discharge from the ED. Information about the medications that were administered in the ED was prepared by checking the actual dosing time on the EMR, not simply the physician’s order list. To protect the privacy of the patients involved, all data were encoded and protected. This study was conducted with the approval of the Institutional Review Board of Kyung Hee University Hospital at Gangdong (IRB No. 2014-08-003) and Gangneung Asan Hospital (IRB No. 2014–046) in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.\n\nEvaluation of PIMs and pDDIs\nPotentially inappropriate medications and pDDIs in the older adults were identiﬁed using a commercially available drug utilization review (DUR) database program in Korea (DIKPlus, FirstDIS Ltd, Seoul, Korea). This DUR program provides information on drug–drug interactions, contraindications, and precautions for special population groups such as older adults, children, as well as pregnant and breastfeeding women. For PIMs and pDDIs in older adults, the database was developed by reviewing the Beers Criteria of the American Geriatric Society and the list of drugs to be used with caution in older patients which is provided by the Korea Food and Drug Administration. In addition, product package inserts, US Hospital Preparation Service (AHFS) medication information, Merck manual, US Food and Drug Administration MedWatch and Health Canada were reviewed. Based on these databases, this DUR program classified PIMs in older patients into two groups according to their severity: contraindications (severity level II) and precautions (severity level I). Potential DDIs were classified into three groups: contraindications (severity level III), severe interactions requiring treatment modification (severity level II), and moderate interactions requiring careful monitoring (severity level I).\n\nIn this study, medications that are inappropriate only at a specific dose, duration of administration, or comorbid conditions were not included because this information could not be identified. Therefore, the PIMs and pDDIs considered in this study were those listed on the references regardless of diagnosis or condition.\n\nStatistical Analysis\nAll the statistical analysis was performed on an ED visit, rather than patient case basis. Categorical variables were summarized as values and percentages, and continuous variables were presented as medians and ranges. To understand the characteristics of the medications administered in ED, a descriptive analysis was performed. Multivariate logistic regression analysis was used to identify the predictors of PIM administration. For each ED visit case, the independent variables in the regression model included patient characteristics, such as sex and age, and visit characteristics, such as the number of medications administered and the length of stay. The dependent variable was the PIM occurrence. Two-sided P-values less than 0.05 were considered as statistically significant. All analyses were performed using SAS.\n\nResults\nCharacteristics of the ED Visit Cases\nTable 1 shows the overall characteristics of the ED visit cases. During the study period, a total of 13,002 ED visit cases by 10,686 patients were reported. Some patients had visited the ED more than once (range, 1–18). The median age for the ED visit cases was 74 years (range, 65–104 years). Out of the total cases, 6094 (46.9%) were male and 6908 (53.1%) were female. The median number of diagnoses and medications administered in EDs was 1 (range, 1–3) and 5 (range, 1–55), respectively. The five most common diseases diagnosed in EDs were “Cerebral infarction, unspecified” (545, 4.2%), “Dizziness and giddiness” (463, 3.6%), “Gastroenteritis and colitis of unspecified origin” (336, 2.6%), “Pneumonia, unspecified” (318, 2.5%) and “Unspecified abdominal pain” (204, 1.6%) (Supplementary Table S1). The average length of ED stay was 196 minutes (range, 1–2208 minutes). After the ED visit, there were 6698 cases of hospitalizations (51.5%) and 6154 cases of discharge (47.4%).\nTable 1 Characteristics of the ED Visit Cases\n\nCharacteristics, No. (%)\tTotal Visit\tVisit with PIMsa\tVisit without PIMa\tP-value\t\nNo. of visits\t13,002 (100.0)\t10,291 (79.1)\t2711 (20.9)\t-\t\nSex\t\nMale\t6094 (46.9)\t4776 (46.4)\t1318 (48.6)\t0.040\t\nFemale\t6908 (53.1)\t5515 (53.6)\t1393 (51.4)\t\t\nAge (year)\t\n65–74\t6569 (50.5)\t5274 (51.2)\t1295 (47.8)\t0.005\t\n75–84\t4891 (37.6)\t3816 (37.1)\t1075 (39.7)\t\n≥ 85\t1542 (11.9)\t1201 (11.7)\t341 (12.6)\t\t\nNo. of diagnoses in ED\t\n1\t12,484 (96.0)\t9888 (96.1)\t2596 (95.8)\t0.440\t\n≥ 2\t518 (4.0)\t403 (3.9)\t115 (4.2)\t\t\nNo. of medications administered in ED\t\n1–5\t7827 (60.2)\t5222 (50.7)\t2605 (96.1)\t< 0.001\t\n6–7\t2324 (17.9)\t2256 (21.9)\t68 (2.5)\t\n≥ 8\t2851 (21.9)\t2813 (27.3)\t38 (1.4)\t\t\nLength of ED stay (minutes)\t\n1–196\t6533 (50.2)\t5065 (49.2)\t1468 (54.1)\t< 0.001\t\n197–299\t3235 (24.9)\t2528 (24.6)\t707 (26.1)\t\n≥ 300\t3234 (24.9)\t2698 (26.2)\t536 (19.8)\t\t\nCondition after ED visit\t\nHospitalization\t6698 (51.5)\t5439 (52.9)\t1259 (46.4)\t< 0.001\t\nHome\t6154 (47.4)\t4714 (45.8)\t1440 (53.1)\t\nDeath\t121 (0.9)\t116 (1.1)\t5 (0.2)\t\nNot assessed\t29 (0.2)\t22 (0.2)\t7 (0.3)\t\nNote:\naEach percentage was calculated out of the total number of corresponding visits.\n\nAbbreviations: ED, emergency department; PIM, potentially inappropriate medication.\n\n\n\n\nAnalysis of PIM Use\nOf the total ED visit cases, 10,291 (79.2%) contained at least one PIM in their ED administered medication. Between the visit cases with PIMs and those without them, there were significant differences in sex, age, number of medications administered, length of ED stay, and post-discharge status (Table 1).\n\nOf the visit cases with at least one PIM, the average number of PIMs administered in ED was 2.7 (range, 1–17). A total of 7355 (71.5%) visits received ≥2 PIMs, and 4584 (44.5%) visits received ≥3 PIMs. There were 303 (2.9%) visit cases with only PIMs of severity II (contraindications) and 8125 (79.0%) visit cases with only PIMs of severity I (precautions). Moreover, 1863 (18.1%) visit cases had PIMs of both severities I and II (Table 2).\nTable 2 Incidence of Visit Cases with PIM\n\nSeverity Level\tNo. of Visit with PIMs (%)\tNo. of PIMs Administered, Average (Range)\t\nII only\t303 (2.9)\t1.2 (1–4)\t\nI only\t8125 (79.0)\t2.5 (1–16)\t\nII and I\t1863 (18.1)\t4.2 (2–17)\t\nAbbreviation: PIM, potentially inappropriate medication.\n\n\n\n\nIn this study, 22 and 219 PIMs corresponding to severity II and I were administered 2615 and 25,343 times, respectively. The five most commonly administered medications are listed in Table 3. The administered PIMs corresponding to severity II in order of the most common were ketorolac (1081, 41.3%), chlorpheniramine (615, 23.5%), midazolam (236, 9.0%), diazepam (197, 7.5%), and triprolidine/pseudoephedrine (114, 4.4%). These five medications accounted for 85.8% of all the severity level II PIMs. Other medications, including methocarbamol, nifedipine (short-acting), amitriptyline, bisacodyl, and piroxicam accounted for a smaller percentage of the total PIMs (Supplementary Table S2). When analyzed in the same way, the administered PIMs corresponding to severity level I in order of the most common were metoclopramide (2606, 10.3%), famotidine (2312, 9.1%), tramadol (1822, 7.2%), acetaminophen (1269, 5.0%) and nitroglycerine (981, 3.9%). These five medications accounted for 35.5% of all the severity level I PIMs. Other medications such as aspirin, heparin, ranitidine, furosemide, fluoroquinolones (ciprofloxacin, levofloxacin), and opioids (pethidine, fentanyl, morphine) followed (Supplementary Table S3).\nTable 3 Top 5 Ranked PIMs\n\nSeverity Level\tMedication\tn (%)a\t\nSeverity II: Contraindications\tKetorolac\t1081 (41.3)\t\nChlorpheniramine\t615 (23.5)\t\nMidazolam\t236 (9.0)\t\nDiazepam\t197 (7.5)\t\n\tTriprolidine/pseudoephedrine\t114 (4.4)\t\nSeverity I: Precautions\tMetoclopramide\t2606 (10.3)\t\nFamotidine\t2312 (9.1)\t\nTramadol\t1822 (7.2)\t\nAcetaminophen\t1269 (5.0)\t\nNitroglycerine\t981 (3.9)\t\nNote:\naEach percentage was calculated out of the total number of administration at each severity level.\n\nAbbreviation: PIM, potentially inappropriate medication.\n\n\n\n\nThe results of the multivariate logistic regression analysis are noted in Table 4. They indicated that female patients were more associated with increased risk of PIM administration than male patients, and this difference was significant [OR 1.13 (1.03–1.23), p = 0.012]. The visits associated with administered medications numbering six to seven and eight or more had higher risks of PIM administration when compared to the control [OR 16.42 (12.85–21.00), p < 0.001; OR 36.23 (26.21–50.09), p < 0.001; respectively] (Figure 1). It was found that the length of ED stay of more than 300 minutes had a significantly higher risk of PIM administration than the control [1.15 (1.02–1.29), p = 0.026]. However, those aged between 75 and 84 were significantly associated with a decreasing odds ratio of PIM administration [OR 0.88 (0.79–0.97), p = 0.008].\nTable 4 Crude and Adjusted Odds Ratios for Factors Influencing PIM Administration\n\nCharacteristics\tCrude Model\tAdjusted Model\t\nOR (95% CI)\tP-value\tOR (95% CI)\tP-value\t\nSex\t\nMale\t1.00 (Reference)\t\t1.00 (Reference)\t\t\nFemale\t1.09 (1.004–1.19)\t0.041\t1.13 (1.03–1.23)\t0.012\t\nAge (years)\t\n65–74\t1.00 (Reference)\t\t1.00 (Reference)\t\t\n75–84\t0.87 (0.80–0.96)\t0.003\t0.88 (0.79–0.97)\t0.008\t\n≥ 85\t0.87 (0.76–0.99)\t0.035\t0.87 (0.75–1.002)\t0.053\t\np-for trend\t\t0.004\t\t0.007\t\nNo. of medications administered in ED\t\n1–5\t1.00 (Reference)\t\t1.00 (Reference)\t\t\n6–7\t16.55 (12.94–21.16)\t< 0.001\t16.42 (12.85–21.00)\t< 0.001\t\n≥ 8\t36.9 (26.71–50.99)\t< 0.001\t36.23 (26.21–50.09)\t< 0.001\t\np-for trend\t\t< 0.001\t\t< 0.001\t\nLength of ED stay (minutes)\t\n1–196\t1.00 (Reference)\t\t1.00 (Reference)\t\t\n197–299\t1.04 (0.94–1.15)\t0.491\t1.01 (0.90–1.12)\t0.903\t\n≥ 300\t1.46 (1.31–1.63)\t< 0.001\t1.15 (1.02–1.29)\t0.026\t\np-for trend\t\t< 0.001\t\t0.029\t\nAbbreviations: ED, emergency department; PIM, potentially inappropriate medication.\n\n\nFigure 1 Relationship between PIM incidence and the number of medications administered in ED.\n\nAbbreviations: PIM, potentially inappropriate medication; ED, emergency department.\n\nAnalysis of pDDIs\nDuring the study period, pDDI between the medications administered in ED was observed in 2668 visit cases (20.5% of the total visit cases). Potential DDIs corresponding to severity III (contraindications), severity II (severe interactions), and severity I (moderate interactions) were reported from 161 visits (1.2%), 607 visits (4.7%), and 1900 visits (14.6%), respectively. The five most commonly administered medication combinations with respect to the three severity levels are listed in Table 5. The medication combinations corresponding to severity III were in the order of the most common ketorolac-aceclofenac (61, 37.9%), ketorolac-celecoxib (32, 19.9%), ketorolac-ibuprofen (20, 12.4%), levofloxacin-amiodarone (12, 7.5%), and esomeprazole-clopidogrel (10, 6.2%). These five combinations accounted for 83.9% of all the severity level III pDDIs (Supplementary Table S4). When analyzed in the same way, the medication combinations corresponding to severity II were in the order of the most common aspirin-heparin (424, 69.9%), levofloxacin-human insulin (31, 5.1%), ciprofloxacin-human insulin (17, 2.8%), amiodarone-diltiazem (13, 2.1%), and amitriptyline-acetaminophen/tramadol (13, 2.1%), and those corresponding to severity I were in the order of the most common aspirin-clopidogrel (510, 26.8%), heparin-clopidogrel (346, 18.2%), atorvastatin-clopidogrel (181, 9.5%), furosemide-candesartan (73, 3.8%), and levofloxacin-budesonide (47, 2.5%) (Supplementary Table S5 and S6).\nTable 5 Top 5 Ranked pDDIs\n\nSeverity Level\tDrug-Drug Interaction\tn (%)a\t\nSeverity III: Contraindications\tKetorolac-aceclofenac\t61 (37.9)\t\nKetorolac-celecoxib\t32 (19.9)\t\nKetorolac-ibuprofen\t20 (12.4)\t\nLevofloxacin-amiodarone\t12 (7.5)\t\n\tEsomeprazole-clopidogrel\t10 (6.2)\t\nSeverity II: Severe interactions\tAspirin-heparin\t424 (69.9)\t\nLevofloxacin-human insulin\t31 (5.1)\t\nCiprofloxacin-human insulin\t17 (2.8)\t\nAmiodarone-diltiazem\t13 (2.1)\t\n\tAmitriptyline-acetaminophen/tramadol\t13 (2.1)\t\nSeverity I: Moderate interactions\tAspirin-clopidogrel,\t510 (26.8)\t\nHeparin-clopidogrel,\t346 (18.2)\t\nAtorvastatin-clopidogrel\t181 (9.5)\t\nFurosemide-candesartan\t73 (3.8)\t\n\tLevofloxacin-budesonide\t47 (2.5)\t\nNote:\naEach percentage was calculated out of the total number of pDDIs at each severity level.\n\nAbbreviation: pDDIs, potential drug–drug interactions.\n\n\n\n\nDiscussion\nTo the best of our knowledge, this is the first DUR study to focus on the appropriateness of the drugs administered in EDs to older Korean patients. There have been a few studies that have evaluated PIMs in older patients in Korea, but all of them were conducted in outpatient settings or long-term care facilities.15–19 This study observed that, of the total ED visit cases by older patients, 79.2% and 20.5% involved at least one PIM and pDDI in the medications administered in ED, respectively. The independent variables of sex, the number of medications administered in ED, and the length of ED stay were significantly associated with PIM administration.\n\nThe overall incidence of PIM administration detected in this study (79.2%) was higher than previous large-scale studies conducted in Western and Asian countries using ED data (15% to 53%).10,20–23 Although Harrison et al reported that 76% of study patients received at least one prescription with PIM according to Beers criteria, the total sample size of their study was small (n = 400).24 The high incidence of the administration of PIMs in this study could be principally explained by the DUR program used in this study, which contains more country-specific medications than the Beers Criteria primarily used in the previous studies. The Beers Criteria has been used to warn of PIM in older patients for a long time, but it is difficult to apply equally to all countries since the available medications and prescription preferences vary by country. In support of this view, Chang et al confirmed that large differences of PIM incidence among older patients in EDs in their study using the Taiwan National Health Insurance Research Database corresponded to differences between country-specific and country non-specific PIM criteria, and they emphasized the importance of establishing country-specific PIM criteria as references for clinical practice in EDs.22\n\nIn this study, the frequently administered PIMs corresponding to severity II (contraindication) were usually symptom relief drugs including ketorolac, chlorpheniramine, benzodiazepines such as midazolam and diazepam, and triprolidine/pseudoephedrine. These results are similar to previous studies.10,21–23 Ketorolac is known to cause gastrointestinal toxicity, and chlorpheniramine may cause sedation and urinary retention due to its anticholinergic activity in the older adults. Benzodiazepines have a sedative effect, and there is a risk of hypotension or paradoxical reactions in the older adults. The current study found that each of the five most frequently administered medications of severity II and I accounted for 85.8% and 35.5% of their total PIMs, respectively. Therefore, it would be very beneficial to encourage ED doctors to consider the risk–benefit ratio before prescribing particularly these drugs, to older patients in ED.\n\nThe multivariate logistic regression analysis in this study identified female patients, the number of medications administered in ED, and the length of ED stay as factors significantly increasing the risk of PIM administration to older patients visiting EDs, and this is consistent with previous studies.10,21 In this regard, previous studies have explained that females are generally more susceptible to inappropriate prescriptions because they are generally at a higher risk of developing several chronic conditions than males.25,26 In addition, female patients are known to use more sleep-inducing drugs, antidepressants, and analgesics than males, because of their higher prevalence of anxiety disorders, depression, and sleep disorders.27 Interestingly, the incidence of PIM administration was reported to be lower in older patients aged between 75 and 84 years than in the control group (aged between 65 and 74). This result could be explained by ED doctors tending to assess the appropriateness of medications more carefully prior to prescribing to older patients. Further research is needed to clarify the reasons for this observation.\n\nPotential DDIs between the medications administered in ED were also evaluated in this study. The pDDI incidence was 20.5% of total visit cases, and the most frequently reported contraindicated drug combinations were ketorolac and other nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac, also the most frequently administered PIM in the current study, can cause serious gastrointestinal problems such as bleeding or peptic ulcers. Its gastrointestinal toxicity is known to be five times stronger than any other NSAID.28 Moreover, ketorolac combinations with other NSAIDs may enhance the risk of gastrointestinal adverse effects.\n\nThe prescriptions given in ED are short-term and one-time doses, and the ED situation is generally more critically urgent than that of any other station. Nevertheless, PIMs or pDDIs should be considered carefully since in older patients they can cause severe adverse effects, even in a single dose. Strategies to promote such caution have been applied over the past decade, such as the development of guidelines for the management of medication of the older patients in EDs or software that automatically generates electronic alerts for PIMs or pDDIs in the prescription process.3 However, their effectiveness at ensuring safe medication prescription and administration has had limitations. For example, it was reported that a high percentage (35–96%) of automatically generated electronic alerts were often ignored by doctors because of inadequate alerts for a specific clinical situation or the intended prescription.29 To improve the situation, a more comprehensive review of prescription drugs based on clinical relevance and a better understanding of the unique medical environment of each country is needed. For this, doctor-pharmacist collaboration in ED may be the answer. Recent studies found that pharmacist-assisted medication reconciliation and integration system or academic detailing of physician residents provided by physician–pharmacist pairs contributed to reduce PIM prescription to older patients in ED practices.30,31\n\nThe strength of the current study was that it was able to accurately and completely collect patient-specific drug administration records and other details during ED visits using the EMR data collected from two large university-affiliated teaching hospitals. In addition, the PIM criteria used in this study contained more country-specific and substantial data than Beers Criteria which is commonly used criteria in Western countries. This allowed other medications that were not identified as potentially harmful by Beers Criteria (for example, opioid analgesics) to be reviewed in this study. Despite these strengths, this study has some limitations which should be interpreted carefully. First, since this study was conducted with ED data from two hospitals, it is difficult to generalize the study results in different environments. Second, although this study evaluated the incidence of PIM administration or pDDI in EDs, it did not evaluate the actual incidence of associated adverse drug reactions. Finally, this study was conducted in 2013. Nevertheless, we believe that the results of this study may help in promoting safe drug use in older patients in EDs, since PIMs and pDDIs are still recognized as important issues, especially in older patients.\n\nConclusion\nThis study demonstrated that older Korean patients were highly exposed to PIMs and medications with pDDIs in the ED. Therefore, healthcare providers in the EDs should carefully consider the risk of administering PMIs or medications with pDDIs, especially when treating female patients, patients who have been prescribed many medications in the ED, and patients who have stayed in the ED for a long time.\n\nAcknowledgments\nThe authors acknowledge the efforts of Department of Pharmacy of Gang Neung Asan Hospital and Kyung Hee University Hospital at Gangdong for collecting clinical data and providing administrative supports.\n\nDisclosure\nThe authors declare no potential conflicts of interests.\n==== Refs\nReferences\n1. Carpenter \nCR , Platts-Mills \nTF . Evolving prehospital, emergency department, and “inpatient” management models for geriatric emergencies\n. Clin Geriatr Med . 2013 ;29 (1 ):31 –47\n. doi:10.1016/j.cger.2012.09.003 23177599 \n2. Hwang \nU , Morrison \nRS . The geriatric emergency department\n. 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Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs\n. Arch Intern Med . 1998 ;158 (1 ):33 –39\n. doi:10.1001/archinte.158.1.33 9437376 \n29. Bajcar \nJM , Wang \nL , Moineddin \nR , Nie \nJX , Tracy \nCS , Upshur \nRE . From pharmaco-therapy to pharmaco-prevention: trends in prescribing to older adults in Ontario, Canada, 1997–2006\n. BMC Fam Pract . 2010 ;11 (1 ):75 . doi:10.1186/1471-2296-11-75 20929561 \n30. Liu \nYL , Chu \nLL , Su \nHC , et al. Impact of computer-based and pharmacist-assisted medication review initiated in the emergency department\n. J Am Geriatr Soc . 2019 ;67 (11 ):2298 –2304\n. doi:10.1111/jgs.16078 31335969 \n31. Moss \nJM , Bryan III \nWE , Wilkerson \nLM , et al. An interdisciplinary academic detailing approach to decrease inappropriate medication prescribing by physician residents for older veterans treated in the emergency department\n. J Pharm Pract . 2019 ;32 (2 ):167 –174\n. doi:10.1177/0897190017747424 29277130\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6336", "issue": "17()", "journal": "Therapeutics and clinical risk management", "keywords": "drug utilization review; drug–drug interactions; emergency department; older adults; potentially inappropriate medications", "medline_ta": "Ther Clin Risk Manag", "mesh_terms": null, "nlm_unique_id": "101253281", "other_id": null, "pages": "173-181", "pmc": null, "pmid": "33642859", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "27459338;31176576;10613941;23177599;16268411;28890140;25958334;31887163;30082816;24746437;26689669;9437376;17916122;29438504;31335969;17870486;32162799;20929561;19111015;26546335;26782849;14678335;24396090;27900070;23949970;29277130;31275497;31806945;20370754", "title": "Potentially Inappropriate Prescriptions to Older Patients in Emergency Departments in South Korea: A Retrospective Study.", "title_normalized": "potentially inappropriate prescriptions to older patients in emergency departments in south korea a retrospective study" }	[ { "companynumb": "KR-JNJFOC-20210527759", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOBENZAPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, 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POTENTIALLY INAPPROPRIATE PRESCRIPTIONS TO OLDER PATIENTS IN EMERGENCY DEPARTMENTS IN SOUTH KOREA: A RETROSPECTIVE STUDY. THER CLIN RISK MANAG. 2021?17:173?181", "literaturereference_normalized": "potentially inappropriate prescriptions to older patients in emergency departments in south korea a retrospective study", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20210520", "receivedate": "20210520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19277465, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]
{ "abstract": "The treatment of Graves' hyperthyroidism (GD) complicated with malignancy is challenging, as anti-thyroid thionamide drugs (ATDs) and anti-cancer chemotherapy are both associated with a risk of neutropenia. Treatment with conventional ATDs, radioactive iodine (RAI) or potassium iodide (KI) was attempted in 8 patients with malignancy (34-80 years of age; 2 males and 6 females) in whom GD had been fortuitously diagnosed during a detailed systematic examination. Three patients requiring surgery were initially treated conventionally with methylmercaptoimidazole (MMI), MMI and KI or RAI (group A; one patient each). The patients became euthyroid on days 17-31 and underwent surgery on days 25-47. RAI therapy was administered to one patient after surgery. The patients were then treated with KI during chemotherapy. Five other patients who did not require surgery were initially treated with 100 mg KI monotherapy (group B). The serum free T4 level declined immediately in all of these patients, and they became euthyroid on days 7-18, remaining almost entirely euthyroid for more than 120 days. Anti-cancer chemotherapy was successfully completed for three of the patients while taking KI, despite the patients experiencing repeated episodes of anti-cancer chemotherapy-induced neutropenia. Our present findings suggest that, in patients with GD and malignancy, MMI + KI or RAI may be required if immediate surgery is scheduled, but KI monotherapy may be worth trying, if anti-cancer chemotherapy is scheduled, thus avoiding the possibility of thionamide-induced neutropenia.", "affiliations": "Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.", "authors": "Okamura\|Ken\|K\|;Bandai\|Sachiko\|S\|;Fujikawa\|Megumi\|M\|;Sato\|Kaori\|K\|;Kitazono\|Takanari\|T\|", "chemical_list": "D013956:Antithyroid Agents; D007457:Iodine Radioisotopes; D011193:Potassium Iodide; D008713:Methimazole", "country": "Japan", "delete": false, "doi": "10.1507/endocrj.EJ20-0016", "fulltext": null, "fulltext_license": null, "issn_linking": "0918-8959", "issue": "67(7)", "journal": "Endocrine journal", "keywords": "Agranulocytosis; Antithyroid drug; Hyperthyroidism; Malignancy; Potassium iodide", "medline_ta": "Endocr J", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D013956:Antithyroid Agents; D005260:Female; D006111:Graves Disease; D006801:Humans; D006980:Hyperthyroidism; D007457:Iodine Radioisotopes; D008297:Male; D008713:Methimazole; D008875:Middle Aged; D009369:Neoplasms; D009503:Neutropenia; D011193:Potassium Iodide; D012307:Risk Factors; D013965:Thyroidectomy", "nlm_unique_id": "9313485", "other_id": null, "pages": "751-758", "pmc": null, "pmid": "32238669", "pubdate": "2020-07-28", "publication_types": "D016428:Journal Article", "references": null, "title": "Clinical experience of treating Graves' hyperthyroidism complicated with malignancy-The possible role of potassium iodide for avoiding the risk of thionamide-associated neutropenia.", "title_normalized": "clinical experience of treating graves hyperthyroidism complicated with malignancy the possible role of potassium iodide for avoiding the risk of thionamide associated neutropenia" }	[ { "companynumb": "JP-MYLANLABS-2020M1076178", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "POTASSIUM IODIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM IODIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POTASSIUM IODIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, RESTARTED AFTER SURGERY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM IODIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOACTIVE IODINE SOLUTION" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIAMAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIAMAZOLE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypothyroidism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMURA K, BANDAI S, FUJIKAWA M, SATO K, KITAZONO T. CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. ENDOCR?J 2020?67(7):751?758.. 2020?67(7):751?758", "literaturereference_normalized": "clinical experience of treating graves hyperthyroidism complicated with malignancy the possible role of potassium iodide for avoiding the risk of thionamide associated neutropenia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200915", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18240696, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "JP-TEVA-2020-JP-1827313", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "POTASSIUM IODIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RESTARTED AFTER SURGERY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM IODIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "POTASSIUM IODIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM IODIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. 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CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. 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"801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypothyroidism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMURA K, BANDAI S, FUJIKAWA M, SATO K, KITAZONO T. CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. 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{ "abstract": "Fusiform dilatation of the internal carotid artery (FDICA) is a well-described radiographic finding following resection of childhood craniopharyngioma (CP). A 39-year-old woman with right-sided FDICA was successfully treated for lesion enlargement with endovascular flow diversion, which has not been described in the literature.", "affiliations": "Department of Neurological Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, United States. Electronic address: [email protected].;Department of Neurological Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, United States.;Department of Neurological Surgery, Division of Neuroradiology, Emory University School of Medicine, Atlanta, GA, United States.;Department of Neurological Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, United States.;Department of Neurological Surgery, Division of Neuroradiology, Emory University School of Medicine, Atlanta, GA, United States.;Department of Radiology and Imaging Sciences, Division of Neuroradiology, Emory University School of Medicine, Atlanta, GA, United States.", "authors": "Reynolds\|Matthew R\|MR\|;Heiferman\|Daniel M\|DM\|;Boucher\|Andrew B\|AB\|;Serrone\|Joseph C\|JC\|;Barrow\|Daniel L\|DL\|;Dion\|Jacques E\|JE\|", "chemical_list": null, "country": "Scotland", "delete": false, "doi": "10.1016/j.jocn.2018.05.006", "fulltext": null, "fulltext_license": null, "issn_linking": "0967-5868", "issue": "54()", "journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia", "keywords": "Craniopharyngioma; Endovascular procedure; Fusiform aneurysm; Internal carotid artery; Stent", "medline_ta": "J Clin Neurosci", "mesh_terms": "D000328:Adult; D002343:Carotid Artery, Internal; D003397:Craniopharyngioma; D004106:Dilatation; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D019635:Neurosurgical Procedures; D010911:Pituitary Neoplasms; D011183:Postoperative Complications", "nlm_unique_id": "9433352", "other_id": null, "pages": "143-145", "pmc": null, "pmid": "29805079", "pubdate": "2018-08", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion-A case report and literature review.", "title_normalized": "fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion a case report and literature review" }	[ { "companynumb": "US-BAYER-2018-138724", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, QOD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "999999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID (} 100 MG)" } ], "patientagegroup": "5", "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subarachnoid haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Platelet aggregation inhibition", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYNOLDS MR, HEIFERMAN DM, BOUCHER AB, SERRONE JC, BARROW DL, DION JE. FUSIFORM DILATATION OF THE INTERNAL CAROTID ARTERY FOLLOWING CHILDHOOD CRANIOPHARYNGIOMA RESECTION TREATED BY ENDOVASCULAR FLOW DIVERSION?A CASE REPORT AND LITERATURE REVIEW. JOURNAL OF CLINICAL NEUROSCIENCE. 2018?54:143?145", "literaturereference_normalized": "fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180731", "receivedate": "20180731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15220934, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "US-DRREDDYS-USA/USA/18/0103070", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTIC DILATATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076273", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTIC DILATATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subarachnoid haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug level above therapeutic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYNOLDS M, HEIFERMAN D, BOUCHER A, SERRONE J, BARROW D, DION J. FUSIFORM DILATATION OF THE INTERNAL CAROTID ARTERY FOLLOWING CHILDHOOD CRANIOPHARYNGIOMA RESECTION TREATED BY ENDOVASCULAR FLOW DIVERSION?A CASE REPORT AND LITERATURE REVIEW. J CLIN NEUROSCI. 2018?54:143?5.", "literaturereference_normalized": "fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion a case report and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180903", "receivedate": "20180903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15343321, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]
{ "abstract": "Background. Network meta-analyses (NMAs) that compare treatments for a given condition allow physicians to identify which treatments have higher or lower probabilities of reducing the risks of disease complications or increasing the risks of treatment side effects. Translating these data into personalized treatment plans requires integration of NMA data with patient-specific pretreatment risk estimates and preferences regarding treatment objectives and acceptable risks. Methods. We introduce a modeling framework to integrate data probabilistically from NMAs with data on individualized patient risk estimates for disease outcomes, treatment preferences (such as willingness to incur greater side effects for increased life expectancy), and risk preferences. We illustrate the modeling framework by creating personalized plans for antipsychotic drug treatment and evaluating their effectiveness and cost-effectiveness. Results. Compared with treating all patients with the drug that yields the greatest quality-adjusted life-years (QALYs) on average (amisulpride), personalizing the selection of antipsychotic drugs for schizophrenia patients over the next 5 years would be expected to yield 0.33 QALYs (95% credible interval [crI]: 0.30-0.37) per patient at an incremental cost of $4849/QALY gained (95% crI: dominant-$12,357), versus 0.29 and 0.04 QALYs per patient when accounting for only risks or preferences, respectively, but not both. Limitations. The analysis uses a linear, additive utility function to reflect patient treatment preferences and does not consider potential variations in patient time discounting. Conclusions. Our modeling framework rigorously computes what physicians normally have to do mentally. By integrating 3 key components of personalized medicine-evidence on efficacy, patient risks, and patient preferences-the modeling framework can provide personalized treatment decisions to improve patient health outcomes.", "affiliations": "Department of Management Science and Engineering, Stanford University, Stanford, CA, USA.;Department of Management Science and Engineering, Stanford University, Stanford, CA, USA.;Center for Primary Care, Harvard Medical School, Boston, MA, USA.", "authors": "Weyant\|Christopher\|C\|0000-0003-2609-9486;Brandeau\|Margaret L\|ML\|;Basu\|Sanjay\|S\|0000-0002-0599-6332", "chemical_list": "D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.1177/0272989X19884927", "fulltext": null, "fulltext_license": null, "issn_linking": "0272-989X", "issue": "39(8)", "journal": "Medical decision making : an international journal of the Society for Medical Decision Making", "keywords": "medical decision making; personalized medicine; schizophrenia", "medline_ta": "Med Decis Making", "mesh_terms": "D014150:Antipsychotic Agents; D003198:Computer Simulation; D003657:Decision Making; D006801:Humans; D000071076:Network Meta-Analysis; D057240:Patient Preference; D057285:Precision Medicine; D019057:Quality-Adjusted Life Years; D018570:Risk Assessment; D012309:Risk-Taking; D012559:Schizophrenia", "nlm_unique_id": "8109073", "other_id": null, "pages": "998-1009", "pmc": null, "pmid": "31707910", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "22927695;17909124;9603539;21268053;28696023;27832461;29649252;27434443;25084808;25992305;26626279;28269836;26009228;28919117;27955666;19884297;23810019;25986470;24968989;29477251;20535326;15916472;22025428;28675302;29146652;10834905;27799749;16595571;31077814;22197518;19744297;25950615;25128056;9008519", "title": "Personalizing Medical Treatment Decisions: Integrating Meta-analytic Treatment Comparisons with Patient-Specific Risks and Preferences.", "title_normalized": "personalizing medical treatment decisions integrating meta analytic treatment comparisons with patient specific risks and preferences" }	[ { "companynumb": "US-OTSUKA-2020_005550", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Weyant C, Brandeau ML, Basu S. Personalizing Medical Treatment Decisions: Integrating Meta-Analytic Treatment Comparisons with Patient-Specific Risks and Preferences. MEDICAL DECISION MAKING. 2019;39(8):998-1009", "literaturereference_normalized": "personalizing medical treatment decisions integrating meta analytic treatment comparisons with patient specific risks and preferences", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19916463, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "Stress-induced changes in pharmacokinetics can significantly alter the plasma levels of some drugs such as clozapine. This report describes the case of a middle-aged man with schizoaffective disorder, bipolar type who showed sustained elevation in clozapine levels 3 days after discontinuation. Before the clozapine levels were drawn, he had developed acute bacterial pneumonia and signs of acute bacterial meningitis followed by neuroleptic malignant syndrome after he received multiple doses of intravenous haloperidol for worsening psychosis and aggressive behavior. Existing literature on this topic is also reviewed to investigate potential reasons for sustained clozapine levels during acute inflammatory stress and neuroleptic malignant syndrome.", "affiliations": "Department of Psychiatry, Good Samaritan Regional Medical Center, Corvallis, Oregon, USA.;Napa State Hospital, 2100 Napa Vallejo Hwy, Napa, CA 94558. [email protected].", "authors": "Wagner\|Abigail\|A\|;Shad\|Mujeeb U\|MU\|", "chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "2155-7780", "issue": "22(4)", "journal": "The primary care companion for CNS disorders", "keywords": null, "medline_ta": "Prim Care Companion CNS Disord", "mesh_terms": "D000208:Acute Disease; D014150:Antipsychotic Agents; D003024:Clozapine; D006801:Humans; D008297:Male; D016920:Meningitis, Bacterial; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D018410:Pneumonia, Bacterial; D011618:Psychotic Disorders", "nlm_unique_id": "101547532", "other_id": null, "pages": null, "pmc": null, "pmid": "32628372", "pubdate": "2020-07-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Relationship Between Clozapine Levels and Acute Inflammatory Stress.", "title_normalized": "relationship between clozapine levels and acute inflammatory stress" }	[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-256148", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75713", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOAFFECTIVE DISORDER BIPOLAR TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AGGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOTIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Antipsychotic drug level increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis bacterial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WAGNER A, SHAD MU. RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. PRIM CARE COMP CNS DISORDERS. 2020?22(4)? JUL", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200811", "receivedate": "20200811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18132646, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-JNJFOC-20200715284", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "015923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOTIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190416", "drugstartdateformat": "102", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALDOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENOXAPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "20190416", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190416", "drugstartdateformat": "102", "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOVENOX" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "20190417", "drugenddateformat": "102", "drugindication": "PNEUMONIA PNEUMOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190416", "drugstartdateformat": "102", "drugstructuredosagenumb": "2000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERIAL SEPSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190418", "drugstartdateformat": "102", "drugstructuredosagenumb": "1750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "20190417", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20190416", "drugstartdateformat": "102", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": 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"drugstructuredosagenumb": "14", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICOTINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS BACTERIAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA PNEUMOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20190416" } }, "primarysource": { "literaturereference": "SHAD M, WAGNER . RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. THE PRIMARY CARE COMPANION TO CNS DISORDERS. 2020?22 (4):.", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200908", "receivedate": "20200717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18037162, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-TEVA-2020-US-1812722", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": 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null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-disease interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "WAGNER A, SHAD MU. RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. PRIM?CARE?COMP?CNS?DISORDERS 2020?22(4):NO PAGINATION.", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200828", "receivedate": "20200812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18142795, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-ACCORD-190932", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": null, 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RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. PRIM CARE COMPANION CNS DISORD. 2020?22(4):19BR02586", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200731", "receivedate": "20200718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18039173, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Our aim is to study unanticipated cardiotoxicity associated with the use of anticancer targeted agents, a problem that remains poorly understood. Using diagnosis codes, we retrospectively identified patients with both hematologic malignancies (HM) and cardiovascular diseases (n = 820 patients). Cardiotoxicity was defined per published criteria. The targeted agents of interest included tyrosine kinase inhibitors, proteasome inhibitors, monoclonal antibodies, and immunomodulatory agents. Patients found with cardiotoxicity (n = 29) were compared with 70 case-matched reference subjects. Median time from targeted therapy exposure to cardiotoxicity was 132 days. A higher percentage of patients had prior exposure to anthracyclines in study versus reference group (65.5 vs. 42.8%, P = 0.04), however, did not stay significant in multivariate analysis. Two variables were significant predictors, prior of DVT/PE and Karnofsky score of ≥ 80% (P ≤ 0.011). Only 2 study group patients died of cardiac causes. Most cardiotoxicity patients (23/29) had remained stable or improved, while 21 patients received further chemotherapy. OS was lower in the study group (P = 0.018) versus the reference group. In conclusion, a small number patients with HM experience unanticipated cardiotoxicity with low related mortality. Risk of cardiotoxicity was significantly associated with history of DVT/PE. Most patients do well, but despite that, their OS is significantly poorer.", "affiliations": "Division of Hematology/Oncology, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL, 32610, USA.;Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.;Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.;Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.;Center for Personalized Diagnostics, Biodesign Inst, Arizona State University, Tempe, AZ, USA.;Division of Hematology/Oncology, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL, 32610, USA. [email protected].", "authors": "Shah\|Chintan\|C\|;Gong\|Yan\|Y\|;Szady\|Anita\|A\|;Sun\|Qian\|Q\|;Pepine\|Carl J\|CJ\|;Langaee\|Taimour\|T\|;Lucas\|Alexandra R\|AR\|;Moreb\|Jan S\|JS\|0000-0001-9330-7500", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": "10.1007/s12012-017-9429-8", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-7905", "issue": "18(2)", "journal": "Cardiovascular toxicology", "keywords": "Cardiotoxicity; Hematologic malignancies; Targeted therapy", "medline_ta": "Cardiovasc Toxicol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D066126:Cardiotoxicity; D005260:Female; D006331:Heart Diseases; D019337:Hematologic Neoplasms; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D020246:Venous Thrombosis", "nlm_unique_id": "101135818", "other_id": null, "pages": "184-191", "pmc": null, "pmid": "29022233", "pubdate": "2018-04", "publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "10637245;11287972;11807147;11870163;15795913;16075055;16862153;17319909;18054041;18415035;18490248;18591451;19520246;19638707;20007921;20842465;22044821;22997448;23623503;24489948;24963043;25433360;25733089;26331915;26671818;26735901;26742998;26771810;26899778;26968791;27081036;27123262;27388042;27800661;27813147;28233150", "title": "Unanticipated Cardiotoxicity Associated with Targeted Anticancer Therapy in Patients with Hematologic Malignancies Patients: Natural History and Risk Factors.", "title_normalized": "unanticipated cardiotoxicity associated with targeted anticancer therapy in patients with hematologic malignancies 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MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH, C.. UNANTICIPATED CARDIOTOXICITY ASSOCIATED WITH TARGETED ANTICANCER THERAPY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES PATIENTS: NATURAL HISTORY AND RISK FACTORS. CARDIOVASCULAR TOXICOLOGY. 2018?18(2):184-191", "literaturereference_normalized": "unanticipated cardiotoxicity associated with targeted anticancer therapy in patients with hematologic malignancies patients natural history and risk factors", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180502", "receivedate": "20180420", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14786574, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-TEVA-2018-US-882639", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "085162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH C, GONG Y, SZADY A, SUN Q, PEPINE CJ, LANGAEE T, ET AL. UNANTICIPATED CARDIOTOXICITY ASSOCIATED WITH TARGETED ANTICANCER THERAPY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES PATIENTS: NATURAL HISTORY AND RISK FACTORS. 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UNANTICIPATED CARDIOTOXICITY ASSOCIATED WITH TARGETED ANTICANCER THERAPY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES PATIENTS: NATURAL HISTORY AND RISK FACTORS. CARDIOVASC-TOXICO 2018?18(2):184-191.", "literaturereference_normalized": "unanticipated cardiotoxicity associated with targeted anticancer therapy in patients with hematologic malignancies patients natural history and risk factors", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180419", "receivedate": "20180419", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14780132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "Isoniazid is an anti-tuberculosis drug, used commonly for treatment and prophylaxis of tuberculosis. Acute isoniazid intoxication is characterized by a clinical triad consisting of metabolic acidosis resistant to treatment with sodium bicarbonate, seizures which may be fatal and refractory to standard anticonvulsant therapy, and coma. Treatment requires admission to the intensive care unit for ventilatory support, management of seizures and metabolic acidosis. Pyridoxine, in a dose equivalent to the amount of isoniazid ingested, is the only effective antidote. We report the successful treatment of two isoniazid intoxication cases: the case of a child developing an accidental acute isoniazid intoxication and an adult case of isoniazid intoxication with the intent of suicide.", "affiliations": "Department of Anesthesiology and Reanimation, Celal Bayar University, Manisa, Turkey.", "authors": "Topcu\|I\|I\|;Yentur\|E A\|EA\|;Kefi\|A\|A\|;Ekici\|N Z\|NZ\|;Sakarya\|M\|M\|", "chemical_list": "D000927:Anticonvulsants; D000995:Antitubercular Agents; D014803:Vitamin B Complex; D002606:Charcoal; D017693:Sodium Bicarbonate; D013874:Thiopental; D011736:Pyridoxine; D003975:Diazepam; D007538:Isoniazid", "country": "United States", "delete": false, "doi": "10.1177/0310057X0503300416", "fulltext": null, "fulltext_license": null, "issn_linking": "0310-057X", "issue": "33(4)", "journal": "Anaesthesia and intensive care", "keywords": null, "medline_ta": "Anaesth Intensive Care", "mesh_terms": "D000138:Acidosis; D000208:Acute Disease; D000293:Adolescent; D000927:Anticonvulsants; D000995:Antitubercular Agents; D002606:Charcoal; D002648:Child; D003128:Coma; D003975:Diazepam; D005260:Female; D005751:Gastric Lavage; D006801:Humans; D007442:Intubation, Intratracheal; D007538:Isoniazid; D011736:Pyridoxine; D012640:Seizures; D017693:Sodium Bicarbonate; D013406:Suicide, Attempted; D013874:Thiopental; D014803:Vitamin B Complex", "nlm_unique_id": "0342017", "other_id": null, "pages": "518-20", "pmc": null, "pmid": "16119496", "pubdate": "2005-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication.", "title_normalized": "seizures metabolic acidosis and coma resulting from acute isoniazid intoxication" }	[ { "companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2022-05209", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202610", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Topcu I, Yentur EA, Kefi A, Ekici NZ et al.. Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication. Anaesth Intensive Care. 2005;33(4):518-20", "literaturereference_normalized": "seizures metabolic acidosis and coma resulting from acute isoniazid intoxication", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20220601", "receivedate": "20220601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20899628, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2022-05207", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202610", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Topcu I, Yentur EA, Kefi A, Ekici NZ, et.al. Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication. Anaesth Intensive Care. 2005;33(4):518-520", "literaturereference_normalized": "seizures metabolic acidosis and coma resulting from acute isoniazid intoxication", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20220601", "receivedate": "20220601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20899632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" } ]
{ "abstract": "BACKGROUND\nTo assess feasibility, acute toxicity, and efficacy of intraventricular methotrexate administered as part of the primary therapy in medulloblastoma.\n\n\nMETHODS\nFrom 2001 to 2007, 240 patients < 22 years from 61 treatment centres were registered. Patients received 2-3 cycles of intraventricular methotrexate with systemic chemotherapy in three different treatment arms of the prospective multicentre trial HIT2000 (150 children > 4 years with metastatic, 59 < 4 years with non-metastatic, 31 < 4 years with metastatic medulloblastoma).\n\n\nRESULTS\n211 patients received an intraventricular access device with a subcutaneous reservoir for the application of chemotherapy. Reservoir-associated complications were documented in 57 (27%) patients, mostly due to infection (n = 32) and reservoir malfunction (n = 19), requiring removal in 39 (18%) patients. Acute neurotoxicity likely associated with intraventricular MTX was observed in 9/202 documented patients. Toxicity was usually mild, apart from one therapy-associated death due to toxic oedema followed by seizures. Of 519 treatment cycles including intraventricular methotrexate, 226 (43%) were reduced or omitted, most frequently due to the absence of an intraventricular device. Survival rates were higher in patients receiving ⩾ 75% of the scheduled intraventricular methotrexate dose compared to those receiving < 75% in both univariate and multivariate models (event-free survival (EFS), 61.5 versus 46.2%, p = 0.004; OS, 75.5% versus 60.4%, p = 0.015; hazard ratio: EFS 1.723, p = 0.016; OS 1.648, p = 0.051).\n\n\nCONCLUSIONS\nIntraventricular methotrexate therapy was feasible and mostly well tolerated. Infections were the most frequent complication. A higher cumulative dose of intraventricular methotrexate was associated with better survival. Further evaluation of efficacy and late effects is warranted.", "affiliations": "Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Woman's and Children's Health, University Hospital Leipzig, Leipzig, Germany.;Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Oncology, University of Wuerzburg, Germany.;Pediatrics III, University Hospital of Essen, Germany.;Department of Pediatric Oncology, University of Wuerzburg, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: [email protected].", "authors": "Pompe\|Raisa S\|RS\|;von Bueren\|André O\|AO\|;Mynarek\|Martin\|M\|;von Hoff\|Katja\|K\|;Friedrich\|Carsten\|C\|;Kwiecien\|Robert\|R\|;Treulieb\|Wiebke\|W\|;Lindow\|Christine\|C\|;Deinlein\|Frank\|F\|;Fleischhack\|Gudrun\|G\|;Kuehl\|Joachim\|J\|;Rutkowski\|Stefan\|S\|", "chemical_list": "D008727:Methotrexate", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0959-8049", "issue": "51(17)", "journal": "European journal of cancer (Oxford, England : 1990)", "keywords": "Brain tumours; Chemotherapy; Intraventricular; Medulloblastoma; Methotrexate; Treatment", "medline_ta": "Eur J Cancer", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007223:Infant; D007239:Infections; D007276:Injections, Intraventricular; D008297:Male; D008527:Medulloblastoma; D008727:Methotrexate; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care; D016016:Proportional Hazards Models; D011446:Prospective Studies; D055815:Young Adult", "nlm_unique_id": "9005373", "other_id": null, "pages": "2634-42", "pmc": null, "pmid": "26346136", "pubdate": "2015-11", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy.", "title_normalized": "intraventricular methotrexate as part of primary therapy for children with infant and or metastatic medulloblastoma feasibility acute toxicity and evidence for efficacy" }	[ { "companynumb": "DE-MYLANLABS-2015M1046321", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "201529", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDULLOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Areflexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "POMPE RS, VON BUEREN AO, MYNAREK M, VON HOFF K, FRIEDRICH C, KWIECIEN R, ET AL. INTRAVENTRICULAR METHOTREXATE AS PART OF PRIMARY THERAPY FOR CHILDREN WITH INFANT AND/OR METASTATIC MEDULLOBLASTOMA: FEASIBILITY, ACUTE TOXICITY AND EVIDENCE FOR EFFICACY. EUR-J-CANCER 2015? 51(17):2634-42.", "literaturereference_normalized": "intraventricular methotrexate as part of primary therapy for children with infant and or metastatic medulloblastoma feasibility acute toxicity and evidence for efficacy", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20151223", "receivedate": "20151223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11862773, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]
{ "abstract": "Eptifibatide is a glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitor which prevents platelet activation. The mechanism in which eptifibatide causes profound thrombocytopenia is poorly understood. One hypothesis suggests antibody-dependent pathways which cause thrombocytopenia upon subsequent reexposure to eptifibatide. This case reports acute profound thrombocytopenia (platelets < 20 × 103/mm3) within 24 hours of administration. Alveolar hemorrhage occurred during a second eptifibatide infusion 5 days after initial asymptomatic eptifibatide treatment. Case Presentation. A 50-year-old male presenting with a STEMI was treated with eptifibatide during cardiac catheterization. Twelve hours posttreatment, the patient encountered profound thrombocytopenia and hemoptysis. The patient was briefly intubated for airway protection. The patient was stabilized after receiving platelet transfusion and fully recovered.\nThis is one of several cases reported on eptifibatide causing acute profound thrombocytopenia and subsequent alveolar hemorrhage. This case supports the theory in which antibodies contribute to eptifibatide-induced thrombocytopenia.", "affiliations": "Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.;Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.;Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.;Michigan State University College of Osteopathic Medicine, 965 Wilson Road, East Lansing, MI 48824, USA.;Michigan State University College of Osteopathic Medicine, 965 Wilson Road, East Lansing, MI 48824, USA.;Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.", "authors": "Byrd\|Gregory\|G\|https://orcid.org/0000-0002-3829-1793;Custovic\|Sabina\|S\|;Byrd\|David\|D\|;Ingrassia Miano\|Deanna\|D\|;Bathla\|Jasdeep\|J\|;Attallah\|Antonious\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2021/8817067", "fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420\n2090-6439\nHindawi\n\n10.1155/2021/8817067\nCase Report\nAcute Profound Thrombocytopenia Induced by Eptifibatide Causing Diffuse Alveolar Hemorrhage\nhttps://orcid.org/0000-0002-3829-1793\nByrd Gregory [email protected]\n1\nCustovic Sabina 1\nByrd David 1\nIngrassia Miano Deanna 2\nBathla Jasdeep 2\nAttallah Antonious 1\n1Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA\n2Michigan State University College of Osteopathic Medicine, 965 Wilson Road, East Lansing, MI 48824, USA\nAcademic Editor: Kenneth S. Waxman\n\n2021\n15 7 2021\n2021 881706723 7 2020\n16 6 2021\nCopyright © 2021 Gregory Byrd et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nEptifibatide is a glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitor which prevents platelet activation. The mechanism in which eptifibatide causes profound thrombocytopenia is poorly understood. One hypothesis suggests antibody-dependent pathways which cause thrombocytopenia upon subsequent reexposure to eptifibatide. This case reports acute profound thrombocytopenia (platelets < 20 × 103/mm3) within 24 hours of administration. Alveolar hemorrhage occurred during a second eptifibatide infusion 5 days after initial asymptomatic eptifibatide treatment. Case Presentation. A 50-year-old male presenting with a STEMI was treated with eptifibatide during cardiac catheterization. Twelve hours posttreatment, the patient encountered profound thrombocytopenia and hemoptysis. The patient was briefly intubated for airway protection. The patient was stabilized after receiving platelet transfusion and fully recovered.\n\nConclusion\n\nThis is one of several cases reported on eptifibatide causing acute profound thrombocytopenia and subsequent alveolar hemorrhage. This case supports the theory in which antibodies contribute to eptifibatide-induced thrombocytopenia.\n==== Body\n1. Introduction\n\nEptifibatide is a glycoprotein IIb/IIIa receptor inhibitor which works to prevent cross-linkage and platelet plug formation. Eptifibatide is used as standard antithrombotic therapy in the management of acute coronary syndrome (ACS) with unstable angina (UA) or non-ST elevation myocardial infarctions (NSTEMI), as well as in those undergoing percutaneous coronary intervention (PCI). Despite clinical efficacy, acute profound thrombocytopenia within 24 hours of treatment may develop with eptifibatide. Diffuse alveolar hemorrhage (DAH), another rare complication of GP IIb/IIIa inhibitor therapy, is diagnosed using typical symptoms of dyspnea and hemoptysis in addition to radiographic changes [1, 2]. Here, we present a case in which eptifibatide causes thrombocytopenia and alveolar hemorrhage upon second exposure.\n\n2. Case Presentation\n\nThis case outlines a 50-year-old male with past medical history significant for diabetes, hypertension, and coronary artery disease (CAD) who presented to the hospital with chest pain. Five days prior, the patient underwent cardiac catheterization with intervention; 3 stents were placed in the left anterior descending artery. Upon presentation, the patient was found to have an inferior-posterior STEMI. He received multiple balloon angioplasties to a 100% occluded first obtuse marginal artery with in-stent thrombosis. At this time, the patient was on aspirin and Ticagrelor. He was further treated with eptifibatide during the catheterization; a double bolus was given during the case and was to be continued for 12 hours thereafter. The patient developed a severe cough and mild-moderate hemoptysis. In subsequent chest X-rays, diffuse opacities were seen, and the patient was eventually intubated for airway protection (Figure 1). The patient's platelets decreased from 370k to 5k within 12 hours. It is worth noting that the patient was treated with eptifibatide during his initial catheterization 5 days prior as well, with no complications. Due to his acute profound thrombocytopenia and persistent hemoptysis, the patient received 1 unit of platelets; the Ticagrelor and eptifibatide were discontinued. Soon after, his platelets began to rebound. In addition, the patient was extubated the following morning. The patient did not require further intervention, made full recovery, and was discharged 9 days later.\n\n3. Discussion\n\nToday, antiplatelet use is standard in patients with ACS undergoing cardiac catheterization. Eptifibatide works by reversibly inhibiting platelet activation by binding to GP IIb/IIIa receptors on the surface of the platelets. The GP IIb/IIIa receptor is an integrin receptor found exclusively on the surface of the platelets. These receptors respond to components such as von Willebrand factor (vWF), fibronectin, and fibrinogen, which in turn activate clotting [3, 4]. After the receptor is activated, it leads to cross-linking of platelets causing aggregation and thus the formation of a thrombus. Eptifibatide acts as a ligand mimetic; it adheres to the GP IIb/IIIa recognition site and blocks vWF, fibronectin, and fibrinogen from binding, ultimately inhibiting platelet aggregation [5]. The GP IIb/IIIa receptor is especially interesting for several reasons. One reason is that it appears to be hidden when the platelet is not activated [3]. Additionally, there is a staggering amount of the receptors on each platelet, an estimated 50,000 receptors/cell, giving platelets a powerful ability to aggregate and form a clot [3]. This is likely the reason why GP IIb/IIIa inhibitors are very successful at inhibiting platelet aggregation (Figure 2).\n\nDrug-induced thrombocytopenia is a known complication of GP IIb/IIIa inhibitors [6, 7]. Acute profound thrombocytopenia, commonly defined as platelets < 20 × 103/mm3 within 24 hours of administration, is a rare complication of eptifibatide [8]. In our patient's case, a drop of platelets from 370k to 5k within 12 hours of eptifibatide reexposure, as well as platelet rebound after eptifibatide discontinuation, leads us to believe that this was an instance of drug-induced thrombocytopenia. Drug-induced thrombocytopenia can be confirmed with serum eptifibatide-dependent platelet-reactive antibody testing; however, these labs were not conducted in this particular case [9].\n\nThe estimated occurrence of thrombocytopenia with eptifibatide use is approximately 3%, and acute profound thrombocytopenia occurs around 0.1-1% [4]. According to a database published by the University of Oklahoma which analyzed cases of eptifibatide-induced thrombocytopenia, only 16 of 34 reported cases had bleeding associated with profound thrombocytopenia. The database specifically noted that 10 of the 16 cases had major bleeding (i.e., melena, gross hematuria, and excessive epistaxis). Six of the 16 cases had minor bleeding or trivial bleeding (i.e., petechiae and purpura) [10].\n\nThe mechanism of how eptifibatide causes thrombocytopenia is currently unknown. Mechanisms involving both antibody-dependent and antibody-independent pathways have been proposed. One review found several independent risk factors for thrombocytopenia, including age > 65, low BMI, and a baseline platelet count of <180k [11]. The fact that thrombocytopenia can occur after the first dose of eptifibatide supports current theories of an antibody-independent pathway. However, there is some data to suggest that there are either naturally occurring antibodies against the ligand binding sites where these antiplatelet molecules act [12, 13]. One review found that 5 out of 5 patients who developed thrombocytopenia had high IgG titers with cross-reactivity to GP IIb/IIIa, while 1 of the 5 patients had high IgG levels prior to eptifibatide administration. This data is suggestive of both mechanisms playing a role [9].\n\nEptifibatide-induced thrombocytopenia is a clinical diagnosis. The clinical picture of eptifibatide-induced thrombocytopenia appears as a rapidly dropping platelet count that is quickly reversed after discontinuation of the drug. The most important differentials to rule out are heparin-induced thrombocytopenia and pseudothrombocytopenia. Most other disorders are easily excluded due to a normal platelet count prior to the administration of the drug. In addition, typically, platelet counts only drop below 20k in eptifibatide-induced thrombocytopenia; other diagnoses rarely dip below this threshold.\n\nAdequate treatment of eptifibatide-induced thrombocytopenia typically only requires removal of the offending agent, and platelets usually recover to near-normal levels within several days [12]. If profound thrombocytopenia is present or clinically significant bleeding occurs, both of which were seen in this patient, platelets may be transfused [12].\n\n4. Conclusion\n\nThis case highlights another example of eptifibatide-induced thrombocytopenia and diffuse alveolar hemorrhage. Furthermore, this case may give more weight to the theory that drug-induced thrombocytopenia is driven by antibodies. Although this case does not prove this theory, it is consistent with the theory, as our patient did not have any adverse effects with his first exposure to eptifibatide.\n\nConsent\n\nConsent was obtained from the patient.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 (a) Approximately 24 hours prior to the development of diffuse pulmonary hemorrhage. (b) After the development of severe cough and hemoptysis which required airway protection through intubation.\n\nFigure 2 Flow chart demonstrating platelet activation via GP IIb/IIIa activation. Eptifibatide and similar drugs (red) inhibit the aggregation pathway by blocking GP IIb/IIIa functionality.\n==== Refs\n1 Sadeghi Ghahrodi M. Mahmoody Y. Sheikhlou H. Aalaei Andabili H. Alveolar hemorrhage: a rare complication of eptifibatide (glycoprotein IIb/IIIa inhibitor) International Cardiovascular Research Journal 2011 5 4 151 152 10.5812/icrj.4369 2-s2.0-84859860793\n2 Mikkilineni H. Bruhl S. R. Colyer W. R. Pandya U. A retrospective analysis and case series of glycoprotein IIb/IIIa inhibitor associated diffuse alveolar hemorrhage: two case reports Cases Journal 2009 2 1, article 8553 10.4076/1757-1626-2-8553 2-s2.0-77953383369\n3 Coller B. S. Platelets and thrombolytic therapy New England Journal of Medicine 1990 322 1 33 42 10.1056/NEJM199001043220107 2-s2.0-0025097994\n4 Graidis C. Golias C. Dimitriadis D. Eptifibatide-induced acute profound thrombocytopenia: a case report BMC Research Notes 2014 7 1 p. 107 10.1186/1756-0500-7-107 2-s2.0-84899478046\n5 Visentin G. P. Liu C. Y. Drug-induced thrombocytopenia Hematology/Oncology Clinics of North America 2007 21 4 685 696 10.1016/j.hoc.2007.06.005 2-s2.0-34547114992 17666285\n6 Bougie D. W. Wilker P. R. Wuitschick E. D. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa Blood 2002 100 6 2071 2076 10.1182/blood.V100.6.2071 12200368\n7 Aster R. H. Curtis B. R. Bougie D. W. Thrombocytopenia resulting from sensitivity to GPIIb-IIIa inhibitors Seminars in Thrombosis and Hemostasis 2004 30 5 569 577 10.1055/s-2004-835677 2-s2.0-7044269109 15497099\n8 Nagge J. Jackevicius C. Dzavik V. Ross J. R. Seidelin P. Acute profound thrombocytopenia associated with eptifibatide therapy Pharmacotherapy 2003 23 3 374 379 10.1592/phco.23.3.374.32107 2-s2.0-0037369974 12627937\n9 Attaya S. Kanthi Y. Aster R. McCrae K. Acute profound thrombocytopenia with second exposure to eptifibatide associated with a strong antibody reaction Platelets 2009 20 1 64 67 10.1080/09537100802592676 2-s2.0-61649127808 19172524\n10 George J. N. Drug-induced thrombocytopenia Annals of Internal Medicine 1998 129 11,_Part_1 886 890 10.7326/0003-4819-129-11_part_1-199812010-00009 9867731\n11 Said S. M. Hahn J. Schleyer E. Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia Clinical Research in Cardiology 2007 96 2 61 69 10.1007/s00392-006-0459-7 2-s2.0-33846897804 17146606\n12 George J. N. Aster R. H. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management Hematology 2009 2009 1 153 158 10.1182/asheducation-2009.1.153 2-s2.0-77949434753 20008194\n13 Tempelhof M. W. Benzuly K. H. Fintel D. Krichavsky M. Z. Eptifibatide-induced thrombocytopenia: with thrombosis and disseminated intravascular coagulation immediately after left main coronary artery percutaneous coronary angioplasty Texas Heart Institute Journal 2012 39 1 86 91 22412237\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2021()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "8817067", "pmc": null, "pmid": "34327026", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "15497099;24564943;9867731;17666285;12200368;17146606;22412237;19172524;2264841;12627937;20008194;19830082", "title": "Acute Profound Thrombocytopenia Induced by Eptifibatide Causing Diffuse Alveolar Hemorrhage.", "title_normalized": "acute profound thrombocytopenia induced by eptifibatide causing diffuse alveolar hemorrhage" }	[ { "companynumb": "US-009507513-2108USA003216", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TICAGRELOR" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICAGRELOR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPTIFIBATIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "020718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "DOUBLE BOLUS,CONTINUED FOR 12 HOURS THEREAFTER", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTEGRILIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary alveolar haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction issue", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BYRD G, CUSTOVIC S, BYRD D, MIANO DI, BATHLA J, ATTALLAH A. ACUTE PROFOUND THROMBOCYTOPENIA INDUCED BY EPTIFIBATIDE CAUSING DIFFUSE ALVEOLAR HEMORRHAGE. CASE REPORTS IN CRITICAL CARE. 2021", "literaturereference_normalized": "acute profound thrombocytopenia induced by eptifibatide causing diffuse alveolar hemorrhage", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210819", "receivedate": "20210819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19719946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-SLATE RUN PHARMACEUTICALS-21US000638", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPTIFIBATIDE" }, "drugadditional": "1", 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, SINGLE (12 HOURS THEREAFTER)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARTERIAL CATHETERISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPTIFIBATIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICAGRELOR." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BYRD G, CUSTOVIC S, BYRD D, MIANO DI, BATHLA J,ATTALLAH A. ACUTE PROFOUND THROMBOCYTOPENIA INDUCED BY EPTIFIBATIDE CAUSING DIFFUSE ALVEOLAR HEMORRHAGE. CASE REPORTS IN CRITICAL CARE. 2021?1?3", "literaturereference_normalized": "acute profound thrombocytopenia induced by eptifibatide causing diffuse alveolar hemorrhage", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19716016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.", "affiliations": "Liver Transplant Unit, Department of Gastroenterology, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Pathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, Barcelona, Spain.;Liver Transplant Unit, Department of Gastroenterology, Bellvitge University Hospital, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, Barcelona, Spain.;Liver Transplant Unit, Department of Pathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.", "authors": "Baliellas\|Carme\|C\|0000-0002-3641-6484;Lladó\|Laura\|L\|0000-0002-3717-3306;Serrano\|Teresa\|T\|0000-0003-4679-2771;Gonzalez-Vilatarsana\|Emma\|E\|;Cachero\|Alba\|A\|;Lopez-Dominguez\|Josefina\|J\|;Petit\|Anna\|A\|;Fabregat\|Joan\|J\|", "chemical_list": "D000906:Antibodies", "country": "United States", "delete": false, "doi": "10.1111/ajt.16689", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "21(11)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "liver allograft function/dysfunction; liver transplantation/hepatology; nical research/practice; rejection: antibody-mediated (ABMR)", "medline_ta": "Am J Transplant", "mesh_terms": "D000906:Antibodies; D005260:Female; D006084:Graft Rejection; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008875:Middle Aged", "nlm_unique_id": "100968638", "other_id": null, "pages": "3775-3779", "pmc": null, "pmid": "34008326", "pubdate": "2021-11", "publication_types": "D002363:Case Reports", "references": null, "title": "Sinusoidal obstruction syndrome as a manifestation of acute antibody-mediated rejection after liver transplantation.", "title_normalized": "sinusoidal obstruction syndrome as a manifestation of acute antibody mediated rejection after liver transplantation" }	[ { "companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-299239", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BALIELLAS C, LLADO L, SERRANO T, GONZALEZ VILATARSANA E, CACHERO A, LOPEZ DOMINGUEZ J ET AL. SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. 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SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY?MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. AM J TRANSPLANT. 2021 MAY 19. 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L, SERRANO T, GONZALEZ?VILATARSANA E, CACHERO A, LOPEZ?DOMINGUEZ J ET AL. SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY?MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. AM J TRANSPLANT. 2021", "literaturereference_normalized": "sinusoidal obstruction syndrome as a manifestation of acute antibody mediated rejection after liver transplantation", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210901", "receivedate": "20210901", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19770539, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Convulsive seizures are known to cause severe cardiopulmonary changes and increased autonomic activity. Limited reports describe peri-ictal cardiac arrhythmias such as atrial fibrillation (AF) with generalized tonic-clonic seizures (GTCS). We present a unique case of a healthy 23-year-old male patient with new onset prolonged AF in the setting of new onset seizures, occurring on three independent occasions. Over two years, our patient had multiple hospitalizations for seizures with an electrocardiogram (ECG) diagnosis of AF made on three different occasions, occurring during his post-ictal state (all within 30 min of seizure onset). These seizures were never captured by electroencephalography (EEG) or witnessed by the medical staff, but were reported by family and/or reviewed on video provided by them. After his first GTCS, his AF persisted and was medically cardioverted. Two additional instances of AF after witnessed GTCS have been captured. After his second unprovoked seizure, an anti-seizure drug (ASD) was prescribed. A multi-disciplinary approach may be adopted to address comorbidities associated with seizures. Aggressive evaluation and treatment should be employed for newly diagnosed and refractory seizure patients associated with arrhythmias, in our case AF. Peri-ictal arrhythmias may be considered a potential marker for increased sudden unexpected death in epilepsy (SUDEP) risk.", "affiliations": "Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Medicine, University of Louisville, 501 East Broadway, Suite 100, Louisville, KY 40202, USA.;Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.;Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.", "authors": "Elnazeir\|Marwa\|M\|;Badugu\|Pradeepthi\|P\|;Narayanan\|Siddharth\|S\|;Hussain\|Abid\|A\|;Bhagat\|Riwaj N M N\|RNMN\|;Jones\|Christopher M\|CM\|;Holiday\|Victoria N\|VN\|;Evans\|Miles S\|MS\|;Palade\|Adriana E\|AE\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ebr.2019.100343", "fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864 Elsevier \n\nS2589-9864(19)30127-3\n10.1016/j.ebr.2019.100343\n100343\nArticle\nGeneralized tonic–clonic seizures with post-ictal atrial fibrillation\nElnazeir Marwa a1 Badugu Pradeepthi b1 Narayanan Siddharth c Hussain Abid c Bhagat Riwaj N.M.N. a Jones Christopher M. c Holiday Victoria N. a Evans Miles S. a Palade Adriana E. [email protected]⁎ a Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA\nb Department of Medicine, University of Louisville, 501 East Broadway, Suite 100, Louisville, KY 40202, USA\nc Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA\n⁎ Corresponding author at: Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA. [email protected] Joint first authors.\n\n\n30 10 2019 \n2020 \n30 10 2019 \n13 10034313 8 2019 18 10 2019 27 10 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Convulsive seizures are known to cause severe cardiopulmonary changes and increased autonomic activity. Limited reports describe peri-ictal cardiac arrhythmias such as atrial fibrillation (AF) with generalized tonic–clonic seizures (GTCS). We present a unique case of a healthy 23-year-old male patient with new onset prolonged AF in the setting of new onset seizures, occurring on three independent occasions. Over two years, our patient had multiple hospitalizations for seizures with an electrocardiogram (ECG) diagnosis of AF made on three different occasions, occurring during his post-ictal state (all within 30 min of seizure onset). These seizures were never captured by electroencephalography (EEG) or witnessed by the medical staff, but were reported by family and/or reviewed on video provided by them. After his first GTCS, his AF persisted and was medically cardioverted. Two additional instances of AF after witnessed GTCS have been captured. After his second unprovoked seizure, an anti-seizure drug (ASD) was prescribed. A multi-disciplinary approach may be adopted to address comorbidities associated with seizures. Aggressive evaluation and treatment should be employed for newly diagnosed and refractory seizure patients associated with arrhythmias, in our case AF. Peri-ictal arrhythmias may be considered a potential marker for increased sudden unexpected death in epilepsy (SUDEP) risk.\n\nHighlights\n• Association of new onset post-ictal atrial fibrillation (AF) with new onset generalized tonic-clonic seizure (GTCS) is rare\n\n• Over a two year period, an overall healthy 23-year-old male was found to have three independent AF occurrences after GTCS\n\n• A multi-disciplinary approach and aggressive treatment with anti-seizure drugs may be adopted to address such events\n\n\n\nKeywords\nAtrial fibrillationSeizuresEpilepsyArrhythmiasEEGECGSUDEP\n==== Body\n1 Introduction\nConvulsive seizures are associated with severe changes in cardiopulmonary activity that can result in central apnea, severe bradycardia and transient asystole [1]. Cardiac rhythm abnormalities such as sinus tachycardia, sinus bradycardia, ictal asystole, ventricular tachycardia (VT), ventricular fibrillation (VF), atrioventricular (AV) nodal block, atrial flutter and atrial fibrillation (AF) can occur during the ictal- and post-ictal phases. Among these, sinus tachycardia was identified as the most common arrhythmia associated with the generalized tonic–clonic seizures (GTCS) [2]. AF, an independent risk factor for stroke and a leading cause of death, is the most prevalent arrhythmia in general and epilepsy populations, with its prevalence relatively higher in men [3] and in patients with temporal lobe epilepsy [4]. However, there are only a few cases in the literature that report AF during the ictal- or post-ictal state [5,6]. We present a unique case of an epilepsy patient having new onset transient AF after his generalized convulsions.\n\n2 Case\nA 23-year-old African-American male with new onset seizure was also found to have new onset transient AF in his postictal period. His past medical history was significant for asthma, obesity (BMI 33.1 kg/m2), and smoking (cigarettes, marijuana). His neurological examination, initial brain imaging, electroencephalography (EEG) and trans-thoracic echocardiogram (ECG) were unremarkable during his first admission for seizure. His first GTCS was at work, described by family as shaking all over, without reported tongue biting, or urinary/bowel incontinence. With unremarkable initial work-up, along with new onset of AF at that time, an initial diagnosis of convulsive syncope was made, with no anti-seizure drug (ASD) being initiated. Subsequent seizures consisted of psychomotor arrest, progressing to GTCS as reported by family/co-workers (patient denied any auras). Hospitalization during the post-ictal phase recorded AF with a rapid ventricular response (RVR) as recorded in the ECG (Fig. 1). Within two days, he spontaneously converted to normal sinus rhythm and was started on apixaban, diltiazem and metoprolol. Follow-up portable cardiac monitoring showed no evidence of recurrent arrhythmia. Beta-blocker and apixaban were discontinued due to symptomatic bradycardia, and respectively low CHA2DS2-VASc score. Multiple prior hospitalizations over a 5-year period for knee-related injuries included an ECG/cardiac monitoring, showing normal sinus rhythm.Fig. 1 AF after the initial GTCS episode. The above EKG demonstrates the AF observed within 30 min, after the initial GTCS episode (August 2017). The heart rate during this period was 116 BPM.\n\nFig. 1\n\nSix months later, levetiracetam was started after the second unprovoked GTCS and changed to valproic acid due to behavioral side effects. Poor compliance led to several admissions after sustaining seizures. During these encounters, multiple 24-hour EEG recording showed mild background slowing and no seizure activity after the anti-seizure medication load. Subsequent brain MRI showed mild asymmetry of hippocampi with no abnormality in the temporal lobes.Fig. 2 EEG during EMU admission (Feb 2019). The EEG of the patient, (A) at the beginning of the seizure episode (the top arrow shows left temporal moderate rhythmic theta activity), and (B) at the end of the seizure (one-minute duration). The heart rate (green), was consistent during episode. The patient did not progress to a GTCS. The two images are at sensitivity 10.\n\nFig. 2\n\nFourteen months after the first seizure, the patient was brought to the emergency department with a prolonged seizure, lasting over 5 min, when the second prolonged AF with RVR was identified. A third seizure associated with AF and RVR prompting hospitalization was captured by family on video and consisted of confusion, right arm tonic posturing, forced head deviation to the right, and progression to a GTCS. A follow-up epilepsy monitoring unit (EMU) recording to determine seizure localization prompting anti-seizure medication discontinuation, captured one focal seizure with left temporal onset and psychomotor arrest but no changes in the cardiac rate or rhythm (Fig. 2). As per EMU protocol, he was immediately treated with lorazepam to avoid secondary generalization and to prevent sudden unexpected death in epilepsy (SUDEP). At this time the patient realized the importance of medication compliance and his epilepsy is currently well controlled with two ASDs.\n\n3 Discussion\nIn convulsive seizures, there is an increased sympathetic activity that is reflected as a peak in catecholamine and electrodermal activity [7]. During the post-ictal state following GTCS, there is an autonomic dysregulation with increased sympathetic and decreased parasympathetic outflow. This may generate fatal arrhythmias and potential SUDEP [7,8]. In addition, the association between arrhythmias and seizures could be due to the direct stimulation of the central autonomic centers [2,9,10]. Seizures originating from the amygdala, hippocampus, insular cortex, and the frontotemporal regions can produce a wide range of cardiac abnormalities [11,12] with studies suggesting that the insular cortex has a direct influence on the cardiac rate and rhythm [4,11]. We observed that our patient had a past history of hypertension and obesity. Cardiovascular comorbidities and their associated risk factors are more common in adults with chronic epilepsy [2,13], particularly those who have a higher incidence of hypertension and obesity. Several of these factors pose a risk towards the development of stroke.\n\nFatal arrhythmias and ECG abnormalities are more likely to be observed during or after a generalized seizure and with prolonged convulsive activity [9,10]. Studies indicate that ictal asystole, VT and VF are associated with SUDEP [7]. Concerns have been expressed over AF compromising ventricular output, and thus could be a precipitating factor for SUDEP [6]. There are very few reports showing post-ictal AF diagnosed during video-EEG monitoring [14]. A study reported a past medical history of AF in two patients with SUDEP but ictal or immediate post-ictal ECG recording in these patients were not available [15]. Clinical evidence showing association between AF and SUDEP is scant and it has been suggested that peri-ictal arrhythmias should be considered as a marker for increased SUDEP risk [7].\n\nWe report three instances of new onset and transient postictal AF after GTCS in our patient, occurring over a period of 24 months. Between his first and second AF associated with seizures events described above, the patient had multiple other seizures prompting five additional ER evaluations or ICU hospitalizations during which AF was not demonstrated on ECG. None of his GTCS occurred while in the hospital, therefore the exact timing of onset of AF in relation to the ictal onset cannot be quantified. It has been hypothesized that following GTCS, there is a period of severe autonomic dysregulation strongly characterized by excessive sympathetic activation in tandem with parasympathetic suppression in the early post-ictal phase; the later phase seems to be dominated by impaired vagal recovery. AF can induce cardiac failure with severe hemodynamic repercussions, and it is a well-known cause of stroke. To our knowledge, a single prior report was published showing post-ictal AF/flutter lasting just minutes as a marker for SUDEP [14]. We considered our patient to have a much higher risk of stroke and/or SUDEP, due to prolonged post-ictal AF, lasting over two days. The post-ictal AF connected with the GTCS presented as an RVR, hence it was important to maintain the sinus rhythm and prevent peripheral embolization [14]. It is worthwhile considering whether or not post-ictal AF needs to be treated, since seizure control in itself is likely to prevent this arrhythmia. An extensive cardiac work-up is vital in these patients to differentiate between peri-ictal AF related to GTCS and those unrelated to seizures. If at all, the risk of SUDEP is unclear, because AF is considered a low-mortality arrhythmia, an implantable cardioverter-defibrillator is not generally indicated, although each case must be individually assessed. A 24-hour Holter ECG is essential to exclude intrinsic cardiac abnormalities [4,11]. Simultaneous video EEG and ECG recordings can establish the relationship between the seizure and the arrhythmia [15].\n\nPatients with AF are at the risk of stroke and systemic embolism without anticoagulant therapy. Seizure control is paramount in all patients, especially if associated with peri-ictal cardiac rhythm abnormalities. ASD selection plays an important role in the patients with intrinsic cardiac conductive tissue dysfunction. Lamotrigine, valproate and gabapentin have a minimal effect on the cardiac function whereas carbamazepine, phenytoin, barbiturates and benzodiazepines are linked with conduction abnormalities [4]. It is vital to closely monitor patients having post-ictal AF after seizures, with primary focus being given to the seizure control. Our patient had a low CHA2DS2-VASc score, therefore the anticoagulation therapy was discontinued. In general, a patient with a high CHA2DS2-VASc score requires anticoagulation therapy. Patients with history of ASD non-compliance or with refractory seizures, that are prescribed anticoagulation therapy, are at risk for prolonged or severe bleeding, especially if they sustain injuries during seizures. Hence, it is important to choose an ASD medication with good efficacy and minimal drug-to-drug interaction and an anticoagulant that can be quickly reversed.\n\n4 Conclusions\nPost-ictal AF, though rarely reported, is a highly dangerous seizure complication. GTCS associated with prolonged arrhythmias such as AF can complicate the healthcare management in patients. AF, when linked with GTCS, has been associated with post-ictal generalized EEG suppression and autonomic dysregulation, and can be potentially connected to SUDEP [14]. A multi-disciplinary approach should be an integral part of AF management if related to seizures, in order to prevent stroke. Aggressive control of the seizures can prevent post-ictal AF occurrence.\n\nThe following is the supplementary data related to this article.Video 1\nThe seizure episode of patient captured by family when the third AF was identified.\n\nVideo 1 \n\nAuthorship of the paper\nP.B., M.E., S.N., and A.P. collected and analyzed the literature, and wrote the manuscript. P.B., M.E., A.H., S.N., and R.B. analyzed the literature. C.J., V.H., M.E., and A.P. reviewed and edited the manuscript. All authors read and agreed to the final version of the manuscript.\n\nEthical statement\nAs referenced by Epilepsy and Behavior Case Reports, all authors report that they have conformed to the principles of ethics in publishing and ethical guidelines for journal publication. Patient consent is provided.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to disclose related to this manuscript.\n==== Refs\nReferences\n1 Ryvlin P. Nashef L. Lhatoo S.D. Bateman L.M. Bird J. Bleasel A. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study Lancet Neurol 12 10 2013 966 977 24012372 \n2 Shmuely S. van der Lende M. Lamberts R.J. Sander J.W. Thijs R.D. The heart of epilepsy: current views and future concepts Seizure 44 2017 176 183 27843098 \n3 Desai R. Rupareliya C. Patel U. Naqvi S. Patel S. Lunagariya A. 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"drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." } ], "patientagegroup": "5", "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Behaviour disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "CHA2DS2-VASc annual stroke risk low", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ELNAZEIR M, BADUGU P, NARAYANAN S, HUSSAIN A, BHAGAT RNMN, JONES CM ET AL. GENERALIZED TONIC-CLONIC SEIZURES WITH POST-ICTAL ATRIAL FIBRILLATION. EPILEPSY AND BEHAVIOR REPORTS. 2020?13:ARTICLE NUMBER 100343. DOI: 10.1016/J.EBR.2019.100343.", "literaturereference_normalized": "generalized tonic clonic seizures with post ictal atrial fibrillation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200422", "receivedate": "20200212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17405272, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]
{ "abstract": "BACKGROUND\nThe aim of this study is to determine the incidence, etiology, clinical characteristics, and outcomes of renal transplant recipients diagnosed and treated for central nervous system (CNS) infection at our institution.\n\n\nMETHODS\nWe analyzed data from all renal transplant recipients between January 2007 and December 2019 that were diagnosed and treated for CNS infections at our institution.\n\n\nRESULTS\nOf 1374 patients who received renal allografts, 13 were diagnosed with CNS infections (9 males), with a mean age of 53.5 years. Patients were diagnosed with CNS infections between 2 months and 11 years after the transplantation. Causative agents included JC virus, Streptococcus pneumoniae, Cryptococcus neoformans, Herpes zoster virus, Mycobacterium tuberculosis, Listeria monocytogenes, and West Nile virus. One patient had concomitant Nocardia and Neisseria infection. Immunosuppression was reduced in all patients. The patient with JC encephalitis and the patient with concomitant Neisseria and Nocardia meningitis died. One patient was returned to dialysis. Other patients recovered with differing levels of neurologic sequelae.\n\n\nCONCLUSIONS\nCentral nervous system infections in renal transplant recipients are rare. However, they are associated with significant morbidity and mortality. A high level of awareness is needed: neurological symptoms may be nonspecific and caused by non-infectious conditions related to the underlying disease, or side-effects of immunosuppressive drugs.", "affiliations": "Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.", "authors": "Basic-Jukic\|Nikolina\|N\|https://orcid.org/0000-0002-0221-2758;Juric\|Ivana\|I\|;Furic-Cunko\|Vesna\|V\|;Kastelan\|Zeljko\|Z\|", "chemical_list": null, "country": "Denmark", "delete": false, "doi": "10.1111/tid.13341", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "22(4)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "CNS infection; cryptococcus", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D020806:Central Nervous System Bacterial Infections; D002494:Central Nervous System Infections; D020805:Central Nervous System Viral Diseases; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D066027:Transplant Recipients", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13341", "pmc": null, "pmid": "32453874", "pubdate": "2020-08", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Central nervous system infections in renal transplant recipients.", "title_normalized": "central nervous system infections in renal transplant recipients" }	[ { "companynumb": "HR-TEVA-2020-HR-1843713", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis pneumococcal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201029", "receivedate": "20201029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18440512, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "HR-TEVA-2020-HR-1843703", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tuberculosis of central nervous system", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Tuberculosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201030", "receivedate": "20201030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18445742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "HR-TEVA-2020-HR-1843714", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis pneumococcal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201029", "receivedate": "20201029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18440595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "HR-TEVA-2020-HR-1843716", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningococcal infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Encephalitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201029", "receivedate": "20201029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18440511, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]
{ "abstract": "BACKGROUND\nThe outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated.\n\n\nOBJECTIVE\nTo assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC.\n\n\nMETHODS\nThis was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis.\n\n\nRESULTS\nSeventy-nine patients were included. Fifty-four patients (68.4%) achieved short-term clinical response and 41 patients (51.9%) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8-26], 33 patients (41.8%) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.12-0.49; p < 0.001]. During a median follow-up of 24 months (IQR 13-34), 9 patients (11.4%) needed colectomy. Short-term response was identified as a predictor of colectomy avoidance (HR 0.14; 95% CI 0.03-0.69; p < 0.007).\n\n\nCONCLUSIONS\nIn UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70% of patients. In the long term, 58% of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86% reduction in the relative risk of colectomy.", "affiliations": "Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Clínico de Santiago, Santiago de Compostela, Spain. [email protected].;Department of Gastroenterology, Hospital Puerta de Hierro, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital de Cabueñes, Gijón, Spain. [email protected].;Department of Gastroenterology, Hospital La Fe, Valencia, Spain. [email protected].;Department of Gastroenterology, Hospital La Paz, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Reina Sofía and IMIBIC, Universidad de Córdoba, Córdoba, Spain. [email protected].;Department of Gastroenterology, Hospital Gregorio Marañón, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital de Fuenlabrada, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Infanta Leonor, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Infanta Sofía, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Gregorio Marañón, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Hospital Universitario Moncloa, Madrid, Spain. [email protected].", "authors": "Taxonera\|Carlos\|C\|;Barreiro-de Acosta\|Manuel\|M\|;Calvo\|Marta\|M\|;Saro\|Cristina\|C\|;Bastida\|Guillermo\|G\|;Martín-Arranz\|María D\|MD\|;Gisbert\|Javier P\|JP\|;García-Sánchez\|Valle\|V\|;Marín-Jiménez\|Ignacio\|I\|;Bermejo\|Fernando\|F\|;Chaparro\|María\|M\|;Ponferrada\|Ángel\|Á\|;Martínez-Montiel\|María P\|MP\|;Pajares\|Ramón\|R\|;de Gracia\|Celia\|C\|;Olivares\|David\|D\|;Alba\|Cristina\|C\|;Mendoza\|Juan L\|JL\|;Fernández-Blanco\|Ignacio\|I\|", "chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab", "country": "United States", "delete": false, "doi": "10.1007/s10620-015-3735-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-2116", "issue": "60(10)", "journal": "Digestive diseases and sciences", "keywords": "Cohort study; Colectomy; Dose escalation; Dose optimization; Infliximab; Ulcerative colitis", "medline_ta": "Dig Dis Sci", "mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003082:Colectomy; D003093:Colitis, Ulcerative; D016001:Confidence Intervals; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "7902782", "other_id": null, "pages": "3075-84", "pmc": null, "pmid": "26044830", "pubdate": "2015-10", "publication_types": "D003160:Comparative Study; D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study", "references": "21122530;22860894;24512909;24758588;16151544;21172214;21133961;23964932;14762776;25989340;25389599;16339095;25083091;19174781;21484965;25117777;24013361;19596014;24121042;20736936;24246151;21466486;22239070;24690137;19651627;21045814;22294554;22062358;23770005", "title": "Infliximab Dose Escalation as an Effective Strategy for Managing Secondary Loss of Response in Ulcerative Colitis.", "title_normalized": "infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis" }	[ { "companynumb": "ES-JNJFOC-20150919564", "fulfillexpeditecriteria": "2", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BECLOMETHASONE DIPROPIONATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BECLOMETHASONE DIPROPIONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colectomy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse drug reaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral thrombosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psoriasis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prostate cancer", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure before pregnancy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAXONERA C, ACOSTA MB, CALVO M, SARO C, BASTIDA G, MARTY N-ARRANZ M, ET AL. INFLIXIMAB DOSE ESCALATION AS AN EFFECTIVE STRATEGY FOR MANAGING SECONDARY LOSS OF RESPONSE IN ULCERATIVE COLITIS. DIG DIS SCI 2015?60 (10):3075-3084.", "literaturereference_normalized": "infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20151016", "receivedate": "20151005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11593919, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "Systemic drug exposure can produce a skin reaction consisting of symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) occurs after systemic exposure to a drug in which the patient was not previously sensitised, either in the first dose or after several doses. The mechanism of SDRIFE is unknown but is hypothesised to be the result of a delayed hypersensitivity response resulting in a cutaneous eruption some days after the exposure to the drug. The diagnosis should be clinical, based on the history and examination, but skin tests can also be performed to confirm sensitisation. But, as always, the gold-standard test is oral provocation. It is important to know this clinical entity to prevent re-exposure to the responsible allergen in the future.", "affiliations": "Allergy Department, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.;Allergy Department, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.;Allergy Department, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.;Nursing Department, Hospital Universitario Nuestra Senora de la Candelaria, Santa Cruz de Tenerife, Spain.", "authors": "Cabrera Hernandez\|Virginia\|V\|;Gonzalez Afonso\|Monica\|M\|;Callero Viera\|Ariel\|A\|http://orcid.org/0000-0002-8964-8262;Martin-Fernandez Martin\|Lidon\|L\|", "chemical_list": "D013256:Steroids; D002981:Clindamycin", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-230077", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(8)", "journal": "BMJ case reports", "keywords": "dermatology; skin; unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000284:Administration, Oral; D001706:Biopsy; D002981:Clindamycin; D003875:Drug Eruptions; D005076:Exanthema; D005260:Female; D006801:Humans; D007402:Intertrigo; D008875:Middle Aged; D013256:Steroids; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31377719", "pubdate": "2019-08-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15606657;30062790;21659857;24001419;25932057;21469762;21469764", "title": "Symmetrical drug-related intertriginous and flexural exanthema due to clindamycin.", "title_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin" }	[ { "companynumb": "ES-BAUSCH-BL-2019-024763", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "050782", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ V, GONZALEZ AFONSO M, CALLERO VIERA A, MARTIN-FERNANDEZ MARTIN L. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. BMJ CASE REPORTS.. 2019?12(8):. DOI:10.1136/BCR-2019-230077", "literaturereference_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190830", "receivedate": "20190830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16761328, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "ES-PFIZER INC-2019369364", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "050162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "150 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ, V.. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. BMJ CASE REPORTS. 2019?12 (8):10.1136/BCR-2019-230077", "literaturereference_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190904", "receivedate": "20190904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16771246, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "ES-EPIC PHARMA LLC-2019EPC00230", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "065194", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYMENOPTERA-SPECIFIC IMMUNOTHERAPY" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROIDS" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SYSTEMIC ANTIHISTAMINES" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ V, GONZALEZ AFONSO M, CALLERO VIERA A, MARTIN-FERNANDEZ MARTIN L. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. BMJ CASE REP. 2019?12(8)", "literaturereference_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190904", "receivedate": "20190904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16771089, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "ES-GLASSHOUSE PHARMACEUTICALS LIMITED CA-2019GLH00007", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROIDS" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209846", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYMENOPTERA-SPECIFIC IMMUNOTHERAPY" }, { "actiondrug": "1", "activesubstance": null, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SYSTEMIC ANTIHISTAMINES" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ V, GONZALEZ AFONSO M, CALLERO VIERA A, MARTIN-FERNANDEZ MARTIN L. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. BMJ CASE REP. 2019?12(8)", "literaturereference_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190904", "receivedate": "20190904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16771792, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "ES-AKORN PHARMACEUTICALS-2019AKN01829", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYMENOPTERA-SPECIFIC IMMUNOTHERAPY" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "065513", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SYSTEMIC ANTIHISTAMINES" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROIDS" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ V, GONZALEZ AFONSO M, CALLERO VIERA A, MARTIN-FERNANDEZ MARTIN L. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. BMJ CASE REP. 2019?12(8)", "literaturereference_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190904", "receivedate": "20190904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16770902, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.", "affiliations": "Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA. [email protected].;Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA.;Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA.;Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA.;Boehringer Ingelheim International GmbH, Biberach, Germany.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.;Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.", "authors": "Cortes\|Jorge\|J\|;Podoltsev\|Nikolai\|N\|;Kantarjian\|Hagop\|H\|;Borthakur\|Gautam\|G\|;Zeidan\|Amer M\|AM\|;Stahl\|Maximilian\|M\|;Taube\|Tillmann\|T\|;Fagan\|Nora\|N\|;Rajeswari\|Sushmita\|S\|;Uy\|Geoffrey L\|GL\|", "chemical_list": "C541363:BI 6727; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000077209:Decitabine; D017346:Protein Serine-Threonine Kinases; C090134:polo-like kinase 1", "country": "Japan", "delete": false, "doi": "10.1007/s12185-020-02994-8", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "113(1)", "journal": "International journal of hematology", "keywords": "AML; Decitabine; PLK1; Phase 1; Volasertib", "medline_ta": "Int J Hematol", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018797:Cell Cycle Proteins; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D064147:Febrile Neutropenia; D001068:Feeding and Eating Disorders; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D058990:Molecular Targeted Therapy; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D016896:Treatment Outcome", "nlm_unique_id": "9111627", "other_id": null, "pages": "92-99", "pmc": null, "pmid": "32951163", "pubdate": "2021-01", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": "24033250;24520204", "title": "Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia.", "title_normalized": "phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia" }	[ { "companynumb": "US-OTSUKA-2020_023610", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VOLASERTIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "350 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "350", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOLASERTIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021790", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MG/M2, DAYS 1?5", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DECITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VOLASERTIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOLASERTIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VOLASERTIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOLASERTIB" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelosuppression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CORTES J, PODOLTSEV N, KANTARJIAN H, BORTHAKUR G, ZEIDAN AM, STAHL M ET AL. PHASE 1 DOSE ESCALATION TRIAL OF VOLASERTIB IN COMBINATION WITH DECITABINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA. INT J HEMATOL. 2021?113 (1):92?9", "literaturereference_normalized": "phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210405", "receivedate": "20201001", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18335764, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Because antithymocyte globulin (ATG) is increasingly used to prevent graft-versus-host disease (GVHD), we performed a retrospective study in adult patients transplanted at our center between January 2008 and December 2012 to explore incidence, characteristics, potential risk factors, and consequences of severe acute hepatotoxicity (SAH) of rabbit ATG (Thymoglobulin) defined as a grade 3 to 4 increase of transaminases. Two hundred twelve patients were included. SAH was diagnosed in 55 patients, representing an incidence of 26%. SAH occurred at a median time of 2 days (range, 1 to 3) after ATG administration, reaching maximum median levels of aspartate aminotransferase and alanine aminotransferase of 8.7 × upper limit of normal (ULN; range, 1.2 to 160) and 11.7 × ULN (range, 4-100), respectively. The International Normalized Ratio was beyond the normal range in 44% of patients. Transaminases decreased below 2 × ULN after a median time of 9 days. We do not report any deleterious impact of SAH on survival, nonrelapse mortality, relapse, or GVHD. Blood systolic pressure < 90 mm Hg during administration of ATG and 2 previous autologous SCT were identified as risk factors for SAH. We believe physicians should be aware of this common toxicity immediately after the administration of ATG to avoid any potential hepatotoxic drug before the resolution and to prevent any risk of hemorrhagic accident.", "affiliations": "Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France. Electronic address: [email protected].;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.", "authors": "Médiavilla\|Clémence\|C\|;Vigouroux\|Stéphane\|S\|;Tabrizi\|Reza\|R\|;Pigneux\|Arnaud\|A\|;Duclos\|Cédric\|C\|;Mohr\|Catherine\|C\|;Robles\|Margot\|M\|;Milpied\|Noël\|N\|", "chemical_list": "D000961:Antilymphocyte Serum; C512542:thymoglobulin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "21(4)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Allogeneic stem cell transplantation; Antithymocyte globulin; Grades 3 to 4 hepatitis", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D064591:Allografts; D000818:Animals; D000961:Antilymphocyte Serum; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D006505:Hepatitis; D006801:Humans; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate", "nlm_unique_id": "9600628", "other_id": null, "pages": "661-5", "pmc": null, "pmid": "25536216", "pubdate": "2015-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin (thymoglobulin) administered before allogeneic stem cell transplantation.", "title_normalized": "transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin thymoglobulin administered before allogeneic stem cell transplantation" }	[ { "companynumb": "FR-SA-2015SA027262", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSULFAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "103869", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THYMOGLOBULIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PREMEDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LESS THAN 4G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXCHLORPHENIRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PREMEDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXCHLORPHENIRAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100UI/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MEDIAVILLA C, VIGOUROUX S, TABRIZI R, PIGNEUX A, DUCLOS C, MOHR C ET AL. TRANSIENT GRADES 3 TO 4 ACUTE HEPATITIS IS A COMMON COMPLICATION OF RABBIT ANTITHYMOCYTE GLOBULIN (THYMOGLOBULIN) ADMINISTERED BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION. BIOL. BLOOD MARROW TRANSPLANT; 2014 OCT 12. 2015;21:661-65. DOI: 10.1016/J.BBMT.2014.12.014.", "literaturereference_normalized": "transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin thymoglobulin administered before allogeneic stem cell transplantation", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20150320", "receivedate": "20150309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10897316, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "BACKGROUND Pituitary metastasis is uncommon, breast and lung cancers being the most frequent primary tumors. Renal cell carcinoma (RCC) is a rare cause of pituitary metastases, with only a few cases described to date. CASE REPORT We report a case of a 61-year-old man who presented with a progressive deterioration of visual acuity and field associated with a bitemporal hemianopsia. Two years ago, he underwent radical right nephrectomy for a clear cell RCC (ccRCC). The biological tests showed pan-hypopituitarism and diabetes insipidus. Brain MRI revealed a large sellar tumor lesion bilaterally infiltrating the cavernous sinuses, which was surgically resected. Histology confirmed a ccRCC pituitary metastasis. The patient received post-surgical radiotherapy. Considering the presence of concomitant extra-pituitary metastases, treatment with sunitinib was started, followed by several lines of therapy with axitinib, everolimus, and sorafenib because of tumor progression. The patient also presented with a pituitary tumor recurrence, which was treated by stereotaxic radiotherapy. He died five years after the initial diagnosis of RCC and 30 months after the diagnosis of the pituitary metastasis. CONCLUSIONS There are no standardized treatment guidelines for management of pituitary metastases. Pituitary surgery plays a role in symptom palliation, and it does not have any relevant impact on survival. Exclusive radiotherapy or stereotaxic radiotherapy could be an alternative to surgery in patients whose general condition is poor or who have concomitant extra-pituitary metastases.", "affiliations": "Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Radiology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Radiotherapy, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.", "authors": "Wendel\|Chloé\|C\|;Campitiello\|Marco\|M\|;Plastino\|Francesca\|F\|;Eid\|Nada\|N\|;Hennequin\|Laurent\|L\|;Quétin\|Philippe\|P\|;Longo\|Raffaele\|R\|", "chemical_list": "D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib", "country": "United States", "delete": false, "doi": "10.12659/ajcr.901032", "fulltext": null, "fulltext_license": null, "issn_linking": "1941-5923", "issue": "18()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000077784:Axitinib; D002292:Carcinoma, Renal Cell; D018450:Disease Progression; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019635:Neurosurgical Procedures; D009536:Niacinamide; D010671:Phenylurea Compounds; D010911:Pituitary Neoplasms; D011758:Pyrroles; D018714:Radiotherapy, Adjuvant; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome", "nlm_unique_id": "101489566", "other_id": null, "pages": "7-11", "pmc": null, "pmid": "28044054", "pubdate": "2017-01-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "4355105;1395423;20694412;14959938;22480977;9647174;24445565;22500201;17541748;22990000;21421711;14764764;24175029;26514360", "title": "Pituitary Metastasis from Renal Cell Carcinoma: Description of a Case Report.", "title_normalized": "pituitary metastasis from renal cell carcinoma description of a case report" }	[ { "companynumb": "PHHY2017FR019187", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLEAR CELL RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201503", "drugenddateformat": "610", "drugindication": "CLEAR CELL RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201412", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to spine", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to pituitary gland", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to the respiratory system", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WENDEL C, CAMPITIELLO M, PLASTINO F, EID N, HENNEQUIN L, QUETIN P ET AL.. PITUITARY METASTASIS FROM RENAL CELL CARCINOMA: DESCRIPTION OF A CASE REPORT. AMERICAN JOURNAL OF CASE REPORTS. 2017;18:7-11", "literaturereference_normalized": "pituitary metastasis from renal cell carcinoma description of a case report", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170212", "receivedate": "20170212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13224428, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "Hyperkalaemia is a potentially life-threatening condition frequently encountered in hospitalised patients. Among the many causes of hyperkalaemia, drugs have often been implicated. In the South African context, with the high burden of HIV, there is an increased incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), and consequently many patients receive high doses of trimethoprim-sulfamethoxazole. A lesser-known side-effect of the trimethoprim component of this combination antibiotic is hyperkalaemia. We report a case in which life-threatening hyperkalaemia developed after institution of high-dose co-trimoxazole for PJP.", "affiliations": "Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. [email protected].", "authors": "Du Plooy\|N\|N\|;Rayner\|B\|B\|", "chemical_list": "D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim", "country": "South Africa", "delete": false, "doi": "10.7196/SAMJ.2019.v109i2.13660", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "109(2)", "journal": "South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde", "keywords": null, "medline_ta": "S Afr Med J", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000900:Anti-Bacterial Agents; D005260:Female; D015658:HIV Infections; D006801:Humans; D006947:Hyperkalemia; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis; D014295:Trimethoprim; D015662:Trimethoprim, Sulfamethoxazole Drug Combination", "nlm_unique_id": "0404520", "other_id": null, "pages": "89-90", "pmc": null, "pmid": "30834857", "pubdate": "2019-01-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Life-threatening hyperkalaemia due to trimethoprim in a patient treated for Pneumocystis jirovecii pneumonia.", "title_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia" }	[ { "companynumb": "ZA-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-204366", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "017377", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "(1600 MG/320MG), QID (6-HOURLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prerenal failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DU PLOOY N, RAYNER B. LIFE-THREATENING HYPERKALAEMIA DUE TO TRIMETHOPRIM IN A PATIENT TREATED FOR PNEUMOCYSTIS JIROVECII PNEUMONIA. S AFR MED J. 2019?109(2):89-90", "literaturereference_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia", "qualification": "3", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16691797, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "ZA-SA-2019SA071024", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1600/320 MG, Q6H", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PRIMAQUINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008316", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRIMAQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prerenal failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DU PLOOY N, RAYNER B.. LIFE-THREATENING HYPERKALAEMIA DUE TO TRIMETHOPRIM IN A PATIENT TREATED FOR PNEUMOCYSTIS JIROVECII PNEUMONIA.. S AFR MED J.. 2019?109(2):89-90", "literaturereference_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia", "qualification": "1", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20190319", "receivedate": "20190318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16084505, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NVSC2019ZA086795", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM GLUCONATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021163", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERKALAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM GLUCONATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (1600 MG/320 MG 6-HOURLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETOXAZOL/TRIMETOPRIM" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PLOOY ND, RAYNER B. LIFE-THREATENING HYPERKALAEMIA DUE TO TRIMETHOPRIM IN A PATIENT TREATED FOR PNEUMOCYSTIS JIROVECII PNEUMONIA. SOUTH AFRICAN MEDICAL JOURNAL. 2019?109(2):89-90", "literaturereference_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia", "qualification": "3", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20200129", "receivedate": "20200129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17343915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200409" } ]
{ "abstract": "Primary biliary cirrhosis (PBC) and multiple sclerosis (MS) are considered autoimmune diseases with a multifactorial aetiology which is thought to be due to a combination of genetic predisposition and environmental triggers. An association of both diseases has been previously described in sporadic case reports. Fingolimod, an antagonist of the sphingosine 1 phosphate receptor family (S1P1/3/4/5), is a promising and effective drug in the treatment of MS. Here we describe a case of PBC like syndrome that was unmasked, concomitantly or consequently to Epstein Barr virus (EBV) infection reactivation, in a 34 year old male patient with relapsing remitting multiple sclerosis who was receiving fingolimod treatment.", "affiliations": "Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi and A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.", "authors": "Marrone\|Aldo\|A\|;Signoriello\|Elisabetta\|E\|;Alfieri\|Gennaro\|G\|;Dalla Mora\|Liliana\|L\|;Rinaldi\|Luca\|L\|;Rainone\|Ilaria\|I\|;Adinolfi\|Luigi Elio\|LE\|;Lus\|Giacomo\|G\|", "chemical_list": "D002756:Cholagogues and Choleretics; D007166:Immunosuppressive Agents; D014580:Ursodeoxycholic Acid; D000068876:Fingolimod Hydrochloride", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1124-9390", "issue": "22(4)", "journal": "Le infezioni in medicina", "keywords": null, "medline_ta": "Infez Med", "mesh_terms": "D000328:Adult; D002756:Cholagogues and Choleretics; D020031:Epstein-Barr Virus Infections; D000068876:Fingolimod Hydrochloride; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008105:Liver Cirrhosis, Biliary; D008297:Male; D009103:Multiple Sclerosis; D012008:Recurrence; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid; D028761:Withholding Treatment", "nlm_unique_id": "9613961", "other_id": null, "pages": "331-6", "pmc": null, "pmid": "25551852", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment.", "title_normalized": "epstein barr virus infection reactivation as a possible trigger of primary biliary cirrhosis like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment" }	[ { "companynumb": "PHHY2015IT001112", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FINGOLIMOD HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022527", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "0.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILENYA" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic steatosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatomegaly", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Biliary cirrhosis primary", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARRONE A, SIGNORIELLO E, ALFIERI G, DALLA MORA L, RINALDI L, RAINONE I,ETC,.,. EPSTEIN BARR VIRUS INFECTION REACTIVATION AS A POSSIBLE TRIGGER OF PRIMARY BILIARY CIRRHOSIS-LIKE SYNDROME IN A PATIENT WITH MULTIPLE SCLEROSIS IN THE COURSE OF FINGOLIMOD TREATMENT. INFEZ MED. 2014;22 (4):331-336", "literaturereference_normalized": "epstein barr virus infection reactivation as a possible trigger of primary biliary cirrhosis like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150116", "receivedate": "20150116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10716342, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "OBJECTIVE\nTo analyze our results with mycophenolate mofetil (MMF) in stable liver transplantation (LT) patients presenting with adverse events (AE) related to prolonged use of calcineurin inhibitors (CNI).\n\n\nMETHODS\nConversion to MMF was performed in 56 out of 323 LT patients from 91-02: 24 (43%) were converted to MMF in monotherapy and 32 (57%) to MMF+low doses of CNI. The indication for conversion was chronic renal insufficiency (CRI) in all patients. The mean time between AE and conversion was 38.7+/-30 months (r: 2-101 m). Post-conversion follow-up was 39+/-20 months (r: 3-72 m).\n\n\nRESULTS\nThe calculated creatinine clearance (Crauckoft), improved significantly in all patients. In those converted to MMF, improvement was seen during the first 18 months for urea and during the first 6 months for creatinine. In patients converted to MMF+CNI, improvement was maintained throughout the conversion period for both urea and creatinine. Eleven (19.6%) patients underwent acute rejection (2 severe episodes in the MMF group and 1 death). Hypertension was present in 31 patients but only improved in 4 (7%). Dyslipemia was found in 12 and improved in 4 (7%). DM was present in 14 and improved in 1 (2%).\n\n\nCONCLUSIONS\nConversion to MMF in monotherapy is useful in stable LT patients with CRI due to CNI, although this result is offset by more severe rejections. Therefore, for AE secondary to CNI, we propose an early conversion to MMF+low doses of CNI as a first step. If liver function remains stable and AEs persist or progress, conversion to MMF in monotherapy is recommended, as a second step, with close monitoring of the patient.", "affiliations": "Liver Transplantation Unit of the Department of General Surgery, Hospital Vall Hebrón, Universidad Autónoma Barcelona, Spain. [email protected] <[email protected]>", "authors": "Bilbao\|Itxarone\|I\|;Castells\|Luis\|L\|;Rojas\|Luis\|L\|;Cancino\|Jorge\|J\|;Dopazo\|Cristina\|C\|;Castro\|Ernest\|E\|;Pou\|Leonor\|L\|;Andino\|Ricardo\|R\|;Margarit\|Carlos\|C\|", "chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D014508:Urea; D003404:Creatinine; D009173:Mycophenolic Acid", "country": "Netherlands", "delete": false, "doi": "10.1016/j.intimp.2006.09.022", "fulltext": null, "fulltext_license": null, "issn_linking": "1567-5769", "issue": "6(13-14)", "journal": "International immunopharmacology", "keywords": null, "medline_ta": "Int Immunopharmacol", "mesh_terms": "D000368:Aged; D065095:Calcineurin Inhibitors; D003404:Creatinine; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006801:Humans; D006973:Hypertension; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007668:Kidney; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011183:Postoperative Complications; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014508:Urea", "nlm_unique_id": "100965259", "other_id": null, "pages": "1977-83", "pmc": null, "pmid": "17161351", "pubdate": "2006-12-20", "publication_types": "D016428:Journal Article", "references": null, "title": "Immunosuppression based on mycophenolate mofetil in stable liver transplanted patients.", "title_normalized": "immunosuppression based on mycophenolate mofetil in stable liver transplanted patients" }	[ { "companynumb": "NVSC2020ES107719", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILBAO I, CASTELLS L, ROJAS L, CANCINO J, DOPAZO C, CASTRO E ET AL. IMMUNOSUPPRESSION BASED ON MYCOPHENOLATE MOFETIL IN STABLE LIVER TRANSPLANTED PATIENTS. 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{ "abstract": "OBJECTIVE\nOptimal treatment strategies for advanced natural killer/T (NK/T)-cell lymphoma have not been fully defined. We compared the safety and efficacy of DDGP and SMILE regimens for advanced NK/T-cell lymphoma in a randomized controlled, multicenter, and open-label clinical trial.\n\n\nMETHODS\nPatients were newly diagnosed in stages III-IV and had performance scores in 0 to 2. Six cycles of DDGP (dexamethasone, cisplatin, gemcitabline, and pegaspargase) or SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy were randomly assigned to them. The primary end point was progression-free survival (PFS). Secondary end points included response rate and overall survival (OS). The trial is ongoing and is registered with ClinicalTrials.gov (No. NCT01501149).\n\n\nRESULTS\nOf 42 patients enrolled, 21 were treated with DDGP therapy, and 21 patients were treated with SMILE therapy. The 1-year PFS and 2-year OS rates were better in the DDGP group than that in the SMILE group (86% vs. 38% for 1-year PFS, P = 0.006; 74% vs. 45% for 2-year OS, P = 0.027). Complete remission (CR) rate and overall response rate (ORR) of the DDGP group were higher than that in the SMILE group (71% vs. 29%, P = 0.005 for CR rate; 95% vs. 67%, P = 0.018 for ORR). The SMILE group showed more serious leucopenia (P = 0.030) and severe allergic reaction (P = 0.015) than the DDGP group. In addition, two cases in the SMILE group underwent grade 4 mucosal reaction.\n\n\nCONCLUSIONS\nDDGP chemotherapy resulted in significant improvement in PFS, OS, and better tolerability compared with SMILE chemotherapy for newly diagnosed advanced NK/T-cell lymphoma patients. Clin Cancer Res; 22(21); 5223-8. ©2016 AACR.", "affiliations": "Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.;Department of Hematology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.;Department of Oncology, Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu, China.;Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China. [email protected].", "authors": "Li\|Xin\|X\|;Cui\|Yingying\|Y\|;Sun\|Zhenchang\|Z\|;Zhang\|Lei\|L\|;Li\|Ling\|L\|;Wang\|Xinhua\|X\|;Wu\|Jingjing\|J\|;Fu\|Xiaorui\|X\|;Ma\|Wang\|W\|;Zhang\|Xudong\|X\|;Chang\|Yu\|Y\|;Nan\|Feifei\|F\|;Li\|Wencai\|W\|;Su\|Liping\|L\|;Wang\|Jinghua\|J\|;Xue\|Hongwei\|H\|;Zhang\|Mingzhi\|M\|", "chemical_list": "D003841:Deoxycytidine; D011092:Polyethylene Glycols; D005047:Etoposide; C042705:pegaspargase; D003907:Dexamethasone; C056507:gemcitabine; D001215:Asparaginase; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1158/1078-0432.CCR-16-0153", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0432", "issue": "22(21)", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "keywords": null, "medline_ta": "Clin Cancer Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002681:China; D002945:Cisplatin; D003841:Deoxycytidine; D003907:Dexamethasone; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D055611:Natural Killer T-Cells; D009364:Neoplasm Recurrence, Local; D011092:Polyethylene Glycols; D012074:Remission Induction; D055815:Young Adult", "nlm_unique_id": "9502500", "other_id": null, "pages": "5223-5228", "pmc": null, "pmid": "27060152", "pubdate": "2016-11-01", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": null, "title": "DDGP versus SMILE in Newly Diagnosed Advanced Natural Killer/T-Cell Lymphoma: A Randomized Controlled, Multicenter, Open-label Study in China.", "title_normalized": "ddgp versus smile in newly diagnosed advanced natural killer t cell lymphoma a randomized controlled multicenter open label study in china" }	[ { "companynumb": "CN-PFIZER INC-2016558439", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG/M2, (DAYS 2-4)", "drugenddate": null, "drugenddateformat": null, "drugindication": "T-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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DDGP VERSUS SMILE IN NEWLY DIAGNOSED ADVANCED NATURAL KILLER/T-CELL LYMPHOMA: A RANDOMIZED CONTROLLED, MULTICENTER, OPEN-LABEL STUDY IN CHINA. 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{ "abstract": "BACKGROUND\nChildhood cancer survivors treated with anthracycline chemotherapy are at an increased risk of long-term cardiac toxicity, and guidelines recommend that exposed survivors undergo echocardiography every 1-5 years. However, it is unclear whether survivors should undergo echocardiographic screening indefinitely, or if a period of echocardiographic stability indicates that screening is no longer necessary. The objective of this study was to evaluate the outcomes of echocardiographic screening to aid in the refinement of existing guidelines.\n\n\nMETHODS\nWe retrospectively analyzed the results of echocardiographic screening in a cohort of adult survivors of childhood cancer treated with anthracyclines and/or cardiac radiation therapy. Interval regression analysis was performed to identify predictors of single-episode or sustained abnormal echocardiograms.\n\n\nRESULTS\nThe cohort constituted 333 survivors, with median follow-up time of 15.8 years post-treatment (range: 5.0-47.9), and median age at treatment of 8 years (range: 1.5-18). Forty-nine survivors had an abnormal echocardiogram (14.7%), and 29 (8.7%) had reproducible abnormal findings. An ongoing continual increase in the incidence of sustained echocardiographic abnormality was seen among patients treated with >250 mg/m(2) doxorubicin at age <5 years, reaching 43% by 20 years of therapy. In contrast, no sustained abnormal echocardiographic findings arose after 10 years of therapy in survivors treated with <250 mg/m(2) at age ≥5 years.\n\n\nCONCLUSIONS\nSingle-episode echocardiographic abnormalities are often not reproduced in subsequent evaluations. The duration of echocardiographic screening for childhood cancer survivors should be reassessed for patients who received lower doses of anthracycline after age 5.", "affiliations": "Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Princess Noorah Oncology Center, King Abdulaziz Medical City, Saudi Arabia.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Adult Cardiology, Toronto Western Hospital, Toronto, Ontario, Canada.;Division of Hematology/Oncology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.", "authors": "Ramjaun\|Aliya\|A\|;AlDuhaiby\|Eman\|E\|;Ahmed\|Sameera\|S\|;Wang\|Lisa\|L\|;Yu\|Eric\|E\|;Nathan\|Paul C\|PC\|;Hodgson\|David C\|DC\|", "chemical_list": "D018943:Anthracyclines", "country": "United States", "delete": false, "doi": "10.1002/pbc.25651", "fulltext": "\n==== Front\nPediatr Blood CancerPediatr Blood CancerpbcPediatric Blood & Cancer1545-50091545-5017Blackwell Publishing Ltd Oxford, UK 10.1002/pbc.25651Research ArticlesEchocardiographic Detection of Cardiac Dysfunction in Childhood Cancer Survivors: How Long Is Screening Required? Ramjaun Aliya MSc1AlDuhaiby Eman MD, FRCPC2Ahmed Sameera MSc1Wang Lisa MSc3Yu Eric MD, FRCPC4Nathan Paul C MD, MSc, FRCPC5Hodgson David C MD, MPH, FRCPC1561 Radiation Medicine Program, Princess Margaret Cancer CentreToronto, Ontario, Canada2 Princess Noorah Oncology CenterKing Abdulaziz Medical City, Saudi Arabia3 Department of Biostatistics, Princess Margaret Cancer CentreToronto, Ontario, Canada4 Division of Adult Cardiology, Toronto Western HospitalToronto, Ontario, Canada5 Division of Hematology/Oncology, The Hospital for Sick Children and University of TorontoToronto, Ontario, Canada6 Department of Radiation Oncology, University of TorontoToronto, Ontario, CanadaCorrespondence to: David Hodgson, Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5E 2M9., E-mail: [email protected] of interest: Nothing to declare.\n\n[The copyright line for this article was changed in October 2015 after original online publication.]\n\n12 2015 06 7 2015 62 12 2197 2203 06 10 2014 09 6 2015 © 2015 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals, Inc.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Background\nChildhood cancer survivors treated with anthracycline chemotherapy are at an increased risk of long-term cardiac toxicity, and guidelines recommend that exposed survivors undergo echocardiography every 1–5 years. However, it is unclear whether survivors should undergo echocardiographic screening indefinitely, or if a period of echocardiographic stability indicates that screening is no longer necessary. The objective of this study was to evaluate the outcomes of echocardiographic screening to aid in the refinement of existing guidelines.\n\nMethods\nWe retrospectively analyzed the results of echocardiographic screening in a cohort of adult survivors of childhood cancer treated with anthracyclines and/or cardiac radiation therapy. Interval regression analysis was performed to identify predictors of single-episode or sustained abnormal echocardiograms.\n\nResults\nThe cohort constituted 333 survivors, with median follow-up time of 15.8 years post-treatment (range: 5.0–47.9), and median age at treatment of 8 years (range: 1.5–18). Forty-nine survivors had an abnormal echocardiogram (14.7%), and 29 (8.7%) had reproducible abnormal findings. An ongoing continual increase in the incidence of sustained echocardiographic abnormality was seen among patients treated with >250 mg/m2 doxorubicin at age <5 years, reaching 43% by 20 years of therapy. In contrast, no sustained abnormal echocardiographic findings arose after 10 years of therapy in survivors treated with <250 mg/m2 at age ≥5 years.\n\nConclusions\nSingle-episode echocardiographic abnormalities are often not reproduced in subsequent evaluations. The duration of echocardiographic screening for childhood cancer survivors should be reassessed for patients who received lower doses of anthracycline after age 5. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.\n\nanthracyclinecardiotoxicitypediatric cancersurvivorship\n==== Body\nINTRODUCTION\nAs survival rates for childhood cancer improve, reducing the long-term toxicities of treatment has emerged as a priority in pediatric oncology. Among the most significant complications of pediatric cancer treatment is the occurrence of cardiac morbidity, occurring in up to 57% of survivors treated with anthracycline chemotherapy.[1] The receipt of radiation therapy (RT) to the heart is also strongly associated with cardiac morbidity in these patients.[2]\n\nRecognizing these risks, expert groups have published consensus-based follow-up guidelines intended to detect early clinical indicators of cardiac dysfunction, with the aim of reducing long-term cardiac morbidity. However, significant limitations in existing echocardiographic screening data have resulted in discordance in surveillance recommendations.[3] The Children's Oncology Group (COG), for example, recommends lifelong echocardiographic screening beginning 2 years post-treatment for survivors treated with anthracyclines and/or mediastinal RT, at a frequency of every 1–5 years, depending on treatment age, anthracycline dose, and RT exposure.[4] In contrast, Scottish Intercollegiate Guidelines recommend screening every 2–3 years for patients at greater risk of anthracycline-induced cardiotoxicity, without recommending a screening duration.[5]\n\nChallenges applying the findings of the existing literature to clinical practice arise for several reasons. Many studies have compared the average ventricular function measures from anthracycline-exposed patients to the average results among non-exposed survivors.[6–10] This approach does not reveal the proportion of anthracycline-exposed survivors who will develop abnormal ventricular function indices over time, for whom screening may be beneficial. Follow-up duration is limited in some studies, so that it is not known whether it is necessary to continue screening indefinitely in all patients, or whether a series of normal echocardiograms indicates that future tests are unlikely to be clinically useful. Consequently, guidelines are inconsistent on the optimal duration of screening. Finally, although high rates of echocardiographic abnormalities have been reported among survivors,[11] many studies report on one-time echocardiographic abnormalities. However, the reproducibility and clinical significance of single-episode abnormalities are uncertain, and the benefit of early detection is inferred largely from elderly patients with complex cardiac pathology.[12–14] Consequently, although routine echocardiographic screening has the appeal of potentially detecting pre-symptomatic heart disease at a time when intervention may prevent further deterioration, it is also possible that for some patients, it is unnecessary and detects abnormalities of no clinical consequence.[15,16]\n\nThe purpose of this study was to help establish optimal use of echocardiographic screening by identifying risk factors associated with sustained echocardiographic abnormalities among pediatric cancer survivors, and to describe the incidence of clinically significant late-onset cardiac morbidity among survivors with an extended post-treatment follow-up.\n\nMETHODOLOGY\nStudy Design and Setting\nThe study cohort comprised adult survivors of pediatric cancer managed in the Aftercare program at the Princess Margaret Cancer Centre in Toronto, Canada. Eligible patients were diagnosed with a malignancy before age 18, had attained age ≥18 years, were treated with anthracyclines and/or cardiac RT, had ≥5 years of follow-up post-treatment, and at least one echocardiogram after 1 year of completing therapy. Date of treatment completion was ascertained through patient chart review (i.e., date of last radiation treatment or final chemotherapy cycle). As the study focus was not acute congestive heart failure, patients with a history of acute ventricular dysfunction arising within 1 year of completing therapy were excluded. The institutional research ethics board of the Princess Margaret Cancer Centre approved the study.\n\nMedical Record Abstraction\nDemographic information, including age at diagnosis, sex, age at treatment completion and length of follow-up, was collected, along with patient data on history of hypertension, diabetes mellitus, and smoking status. Anthracyclines included doxorubicin, daunomycin, and epirubicin. Anthracycline doses were converted to doxorubicin-equivalent dose using a conversion factor of 0.83 for daunomycin and 0.67 for epirubicin.[17]\n\nEchocardiography\nAll echocardiograms were performed at a tertiary cardiac care center according to the Ontario Cardiac Care Network Quality Standards.[18] Echocardiography was ordered using a risk-based frequency defined in the follow-up guidelines of the Children's Oncology Group.[4] Echocardiographic parameters, obtained from original reports, included ejection fraction (EF) and shortening fraction (SF). An echocardiogram was considered abnormal if EF <55% or SF <28%[19] or if valvular abnormalities were described as more than “trivial.” Patients with significant abnormalities were referred to a cardiologist for further management. Survivors were considered to have “any” abnormality when there was at least one abnormal echocardiogram, regardless of subsequent echocardiographic results. A “sustained” abnormality was defined as an abnormal echocardiogram followed by one or more consecutive abnormal echocardiograms.\n\nStatistical Analysis\nChi-square tests were performed to compare categorical variables and two sample t-tests were used to assess continuous variables. Interval regression analyses were performed to identify predictors of time to any abnormal echocardiogram, and to sustained abnormal echocardiograms. This method fits a parametric model to failure time data that can be right, left, or interval-censored, and accounts for cases in which the initial abnormal echocardiogram was found at the first visit, and also for variation in timing and frequency of echocardiography among patients in different risk groups. The following variables were assessed through bivariate analysis: age, anthracycline dose, number and frequency of echocardiograms performed, RT receipt, smoking status and a history of hypertension described in the medical record. Variables ultimately included in multivariate analyses were selected on the basis of statistical significance, clinical importance, and confounding. The incidence of abnormal echocardiography was estimated using interval censoring and plotted based on a nonparametric maximum likelihood estimator using Turnbull's algorithm.[20] All analyses were performed using SAS (version 9.3: SAS Institute, Cary, NC). Plots were produced using R statistical software.[21]\n\nRESULTS\nFour hundred and twenty-one patients met inclusion criteria. Seventy-nine were excluded as they had no echocardiographic data available, and nine were excluded due to incomplete and/or missing data on treatment-related variables. Excluded patients were more likely to have leukemia than included patients (44% vs. 30%) and less likely to have lymphoma (36% vs. 47%, P = 0.02 for difference in diagnoses), were more likely to be ≥5 years old at diagnosis (85% vs. 67%, P = 0.001), but did not differ significantly with respect to cumulative anthracycline dose (P = 0.27). The remaining 333 survivors were analyzed.\n\nPatient demographic and clinical characteristics are summarized in Table I. Overall, 224 (67.3%) of those included in the study were ≥5 years of age at the time of initial cancer treatment. The majority of patients (69.1%) were treated with a doxorubicin-equivalent dose <250 mg/m2 and 130 (39%) patients received thoracic RT (median prescribed dose = 15 Gy, range 10–45 Gy). The mean doxorubicin-equivalent dose was significantly higher in patients with sustained abnormal echocardiography at 295 mg/m2 (P < 0.001). The median number of echocardiograms performed was 2 (range: 1–13), with 96 patients having one echocardiogram. The median follow-up time post-treatment was 15.8 years (range: 5.0–47.9 years). The median interval between the end of treatment and the first echocardiogram was 5.7 years (range 0.9–48.0 years) and the median interval between echocardiograms was 2.2 years (range 0.1–19.4 years). Following an abnormal echocardiogram, the median interval to the next echocardiogram was 1.5 years.\n\nTABLE I Demographics, Treatment and Follow-Up Characteristics\n\n\t% (N) or mean (SD)\t\nAge, mean (SD)\t8.47 (4.92)\t\n 1–4 years, % (No.)\t32.73 (109)\t\n ≥5 years, % (No.)\t67.27 (224)\t\nMale sex, % (No.)\t49.25 (164)\t\nDiagnosis, % (No.)\t\t\n Hodgkin lymphoma\t35.44 (118)\t\n ALL\t43.54 (145)\t\n Wilm tumor\t10.21 (34)\t\n Ewing sarcoma\t3.90 (13)\t\n Osteosarcoma\t3.30 (11)\t\n Rhabdomyosarcoma\t2.10 (7)\t\n Lymphoma\t0.60 (2)\t\n Undifferentiated sarcoma\t0.60 (2)\t\n Angiosarcoma\t0.30 (1)\t\nDoxorubicin dose (mg/m2), mean (SD)a\t212.9 (103.52)\t\nRadiotherapy receipt, % (No.)b\t39.04 (130)\t\nAge x Anthracycline Dose, % (No.)\t23.12 (77)\t\n 1–4 years + 1–250 mg/m2\t9.61 (32)\t\n 1–4 years + ≥250 mg/m2\t52.55 (175)\t\n ≥5 + 1–250 mg/m2\t14.71 (49)\t\n ≥5 + ≥ 250 mg/m2\t10.51 (35)\t\n Any age + no anthracycline\t\t\nConventional cardiac risk factors\t\t\n Smoking (former)\t3.3 (11)\t\n Smoking (current at last follow-up)\t10.2 (34)\t\n Hypertension (ever)\t3.6 (13)\t\n Diabetes (ever)\t2.1 (7)\t\nNo. echocardiograms, mean (SD)c\t2.86 (2.10)\t\na Anthracycline drugs included doxorubicin, daunomycin, and epirubicin. Anthracycline doses were converted to doxorubicin equivalent dose by using conversion factor 0.83 for daunomycin and 0.67 for epirubicin.\n\nb Radiation received by the heart.\n\nc Number of echocardiograms received.\n\nAny Echocardiographic Abnormality\nForty-nine patients (14.7%) had at least one abnormal echocardiogram during the follow-up period. The median time to first abnormal echocardiogram was 11.7 years post-treatment (range: 1.8–42.0 years). The probability of having any echocardiographic abnormality steadily increased and reached 20% by 20 years (Fig. 1). Thirty-nine (79.5%) and 28 patients (57.1%) had an abnormality in EF and SF, respectively. Three patients (6.1%) had a valvular abnormality.\n\nFig. 1 (A) Probability of producing an abnormal echocardiogram. (B) Probability of producing an abnormal sustained echocardiogram.\n\nThe 10-year probabilities of having an abnormal echocardiogram among patients, <250 mg/m2 and ≥250 mg/m2 were 8.3% (95% CI = 4.2–12.3%) and 23.3% (95% CI = 12.5–32.7%), respectively. By 20 years after treatment, these rates were 19.5% (95% CI = 8.3–29.2%) and 36.9% (95% CI = 22.8–48.4%), respectively (P < 0.001, Fig. 2). No echocardiographic abnormalities were noted in the first 20 years of follow-up among patients treated with thoracic RT without anthracyclines. The results of univariate interval regression analyses indicated that an anthracycline dose ≥250 mg/m2 was associated with a significantly greater risk of having any abnormal echocardiogram (P < 0.01; Table II). In multivariate analysis, this association remained statistically significant (P < 0.01; Table II). Receipt of mediastinal RT was not significantly associated with abnormal findings.\n\nFig. 2 Cumulative incidence of abnormal echocardiography stratified by age at treatment (A,B) and by anthracycline dose (C,D).\n\nTABLE II Univariate and Multivariate Interval Regression Analyses for any Abnormal Echocardiogram\n\n\tUnivariate\tMultivariate\t\n\tCoefficientb (95% CI)\tP-value\tCoefficient (95% CI)a\tP-value\t\nAge category\t\t\t\t\t\n Age ≥5 years\tReference\t—\tReference\t—\t\n Age <5 years\t−0.54 (−1.13, 0.046)\t0.0711\t−0.34 (−0.85, 0.17)\t0.186\t\nAnthracycline dose\t\t\t\t\t\n None\tReference\t−\tReference\t−\t\n 1–250 mg/m2\t−1.10 (−2.32, 0.12)\t0.0783\t0.97 (−2.23, 0.29)\t0.130\t\n ≥250 mg/m2\t−2.06 (−3.34, −0.77)\t<0.01\t−1.95 (−3.26, −0.64)\t<0.01\t\nNo. of echocardiogramsb\t0.15 (−0.059, 0.35)\t0.163\t—\t—\t\nEchocardiogram frequency\t0.041 (0.0085, 0.074)\t0.014\t—c\t—\t\nRT receipt\t\t\t\t\t\n No RT\tReference\t—\tReference\t—\t\n RT received\t0.50 (−0.065, 1.06)\t0.083\t0.27 (−0.26, 0.81)\t0.312\t\nSmoking status\t\t\t\t\t\n Never smoked\tReference\t—\t—\t—\t\n Ever smoked\t−0.20 (−0.93, 0.53)\t0.590\t—\t—\t\nHypertension\t\t\t\t\t\n Non-hypertensive\tReference\t—\t—\t—\t\n Hypertensive\t−0.27 (−1.29, 0.75)\t0.6002\t—\t—\t\nDiabetes\t\t\t\t\t\n Non-diabetic\tReference\t—\t—\t—\t\n Diabetic\t0.40 (−1.47, 2.27)\t0.6733\t—\t—\t\na A negative coefficient indicates an increased likelihood of having an abnormal echocardiogram (i.e., reduced time to abnormal echocardiography).\n\nb Number of normal echocardiograms prior to first abnormal echocardiogram.\n\nc Echocardiogram frequency was not significant after adjusting for age and treatment and was therefore omitted from the final model.\n\nThe 10-year probabilities of abnormal echocardiography among patients ages 1–4 years and ≥5 years at the time of treatment were 13.6% (95% CI = 6.6–20.1%) and 10.9% (95% CI = 5.9–15.5%), respectively. By 20 years after treatment, these rates had increased to 26.7% (95% CI = 15.7–36.2%) and 14.5% (95% CI = 7.9–20.7%), respectively (Fig. 2). Although the incidence of abnormal echocardiograms in the younger group increased steadily during this 20-year period, few abnormal echocardiograms were observed beyond 15 years in those receiving chemotherapy at ≥5 years of age. Age <5 years at treatment had a borderline association with developing an abnormal echocardiogram (P = 0.07), but this was not significant in multivariate analysis (Table II). When stratified by age and anthracycline dose, the 20-year rates abnormal echocardiography were 11% (≥5 years + <250 mg/m2), 18% (<5 + <250 mg/m2), 29% (≥5 years + ≥250 mg/m2), and 49% (<5 years + ≥250 mg/m2, P = 0.01).\n\nSustained Echocardiographic Abnormality\nTwenty-nine patients (8.7%) had sustained abnormal echocardiography. For nine patients (2.7%), the results of only one echocardiogram were retrievable, and therefore, we were unable to determine whether abnormal echocardiography was sustained or not. This means there were, at minimum, 11 patients with non-sustained abnormal echocardiography, none of which received any cardiac pharmacologic treatment that could account for subsequent normal echocardiography. The 20-year probability of having a sustained echocardiographic abnormality was 15.7% (95% CI = 11–21%; Fig. 1). Younger treatment age and anthracycline dose ≥250 mg/m2 were significantly associated with the development of sustained echocardiographic abnormalities in both univariate and multivariate analyses (P = 0.032; Table III). The 20-year probabilities of having sustained abnormal echocardiography among patients receiving 0 mg/m2, <250 mg/m2, and ≥250 mg/m2 were 0%, 10.2%, and 35.5%, respectively. Over the entire follow-up duration, there was a consistent increase in the incidence of sustained echocardiographic abnormalities among individuals that received ≥250 mg/m2, whereas the probability of having a sustained abnormal echocardiogram may have plateaued by year 15 in the <250 mg/m2 group (Fig. 2).\n\nTABLE III Univariate and Multivariate Interval Regression Analyses for Sustained Abnormal Echocardiograms Only\n\n\tUnivariate\tMultivariate\t\n\tCoefficientb (95% CI)\tP-value\tCoefficient (95% CI)a\tp-value\t\nAge category\t\t\t\t\t\n Age ≥5 years\tReference\t—\tReference\t—\t\n Age <5 years\t−0.89 (−1.64, 0.15)\t0.019\t−0.72 (−1.37, −0.06)\t0.033\t\nAnthracycline dose\t\t\t\t\t\n None\tReference\t—\t—\t—\t\n <250 mg/m2\t−0.99 (−2.47, 0.50)\t0.194\t−0.96 (−2.53, 0.61)\t0.229\t\n ≥250 mg/m2\t−2.10 (−3.65, −0.56)\t<0.01\t−2.10 (−3.72, −0.48)\t0.011\t\nNo. of echocardiogramsb\t−0.042 (−0.22, 0.13)\t0.64\t—\t—\t\nEchocardiogram frequency\t0.062 (0.019, 0.11)\t<0.01\t—c\t—\t\nRT receipt\t\t\t\t\t\n No RT\tReference\t—\tReference\t—\t\n RT received\t0.19 (−0.41, 0.79)\t0.53\t−0.028 (−0.60, 0.55)\t0.925\t\nSmoking status\t\t\t\t\t\n Never smoked\tReference\t—\t—\t—\t\n Ever smoked\t−0.59 (−1.32, 0.14)\t0.114\t—\t—\t\nHypertension\t\t\t\t\t\n Non-hypertensive\tReference\t—\t—\t—\t\n Hypertensive\t−0.70 (−1.70, 0.30)\t0.172\t—\t—\t\nDiabetesd\t\t\t\t\t\n Non-diabetic\tReference\t—\t—\t—\t\n Diabetic\t—\t—\t—\t—\t\na A negative coefficient indicates an increased likelihood of having an abnormal echocardiogram or reduced time to abnormal echocardiography.\n\nb Number of normal echocardiograms prior to first abnormal echocardiogram.\n\nc Echocardiogram frequency was not significant in multivariable analysis with age and treatment exposures, and therefore was excluded from the final model.\n\nd A univariate analysis was not performed with the diabetes variable as no sustained echocardiogram abnormalities were present in individuals with a positive diabetes status.\n\nThe 20-year probabilities of having sustained abnormal echocardiograms among patients aged 1–4 and patients ≥5 years at treatment were 26.2% and 6.9%, respectively. Few events were observed in the older age group beyond 15 years (Fig. 2).\n\nWhen stratified by age and dose, there was a significant (P = 0.01) difference in the risk of having sustained abnormal echocardiography, which was greatest in younger patients that received a high anthracycline dose (20-year risk = 54%, 95% CI = 27–70%; Fig. 3). In contrast, few events occurred among the 162 patients treated with <250 mg/m2 at age ≥5, where the probability of having an abnormal echocardiogram may have plateaued at 5% (95% CI = 1–9%) after 10 years, with no additional sustained abnormalities occurring among the 109 echocardiograms done beyond 10 years post-treatment in this group.\n\nFig. 3 Cumulative incidence of abnormal echocardiography stratified by age at treatment (A) and by anthracycline dose (B).\n\nAdditional Investigations and Medical Interventions\nThirty-five patients (10.4% of all patients) with abnormal echocardiography were referred to a cardiologist. Twenty-four patients underwent additional investigations (e.g., stress echocardiography ± Holter monitoring) following abnormal echocardiography. Sixteen patients (32.6% of those with abnormal echocardiography, 4.8% of the entire cohort) received a medical intervention. Specifically, 13 patients were prescribed angiotensin converting enzyme inhibitors, 10 were prescribed beta blockers, and two were given diuretic medications. Calcium-channel blockers, statins, and digoxin were also prescribed. Nine (69.2%) of these patients were <5 years of age at the time of treatment. Two patients were admitted to hospital for cardiac-related complications. The median time to the initiation of any cardiac treatment was 12.5 years (range: 3.5–47.2 years) post-treatment. No patients died during the course of follow-up.\n\nDISCUSSION\nNon-invasive and widely available echocardiography remains the recommended screening instrument for cardiac abnormalities in childhood cancer survivors.[4] These recommendations are largely based on studies that report a decrement in the average echocardiographic indices of ventricular function among anthracycline-exposed survivors compared to non-exposed survivors.[6,7,22] Although this method of reporting is useful to elucidate factors associated with overall decline in average cardiac performance, it does not provide insight into the proportion of patients likely to benefit from periodic echocardiographic screening. Moreover, there are no data to establish appropriate cardiac screening duration, and existing guidelines make different recommendations on this issue. Our clinical impression is that for many anthracycline-treated patients, indefinite screening is of limited value, but there have been no clinical studies to elucidate the appropriate time to discontinue screening.\n\nOur finding that young age at exposure and higher anthracycline doses (≥250 mg/m.2) were predictive of the risk of abnormal echocardiography is consistent with prior work,[2,23,24] as well as the risk stratification seen across various guidelines. These findings support the use of continued screening among long-term survivors, particularly those exposed to ≥250 mg/m2 prior to age 5, as the incidence of echocardiographic abnormalities continues to rise for at least 25 years post-treatment, with over half of survivors developing sustained evidence of ventricular dysfunction. In contrast, none of the patients treated with <250 mg/m2 after age 5 developed sustained evidence of ventricular dysfunction beyond 10 years of screening. In our cohort, this subgroup accounted for 51.6% of the study population. If these patients could be discharged from routine echocardiographic screening, it would produce a significant reduction in their burden of follow-up, in addition to saving the costs of unnecessary testing.\n\nThe findings of this clinical study are consistent with the results of recent economic simulation studies.[25,26] Wong et al. modeled the cost-effectiveness of different echocardiograph screening schedules for a variety of anthracycline-exposed patient risk-profiles, and estimated that echocardiographic screening at 2-year intervals among patients ≥5 years at diagnosis treated with an anthracycline dose <300 mg/m2, without RT, could be expected to increase per-person life expectancy by less than 3 months, at a cost of $235,000/QALY.[25] Yeh et al. reported similar findings, where the most cost-effective screening strategy in this relatively low-risk group was no assessment.[26] Taken together, it appears that there is an emerging body of evidence that beyond 10 years after exposure, echocardiography is not clinically useful or cost-effective in patients treated with less than 250 mg/m2 after age 5.\n\nStudies in other clinical settings have also shown that as a diagnostic test, echocardiographic results can be user-dependent, and therefore not always reproducible.[27] Our findings further illustrate this limitation of echocardiography as a screening modality, where only 72% of patients with abnormal echocardiography had reproducible results. This illustrates a limitation of some studies that have reported high rates of single-episode echocardiographic abnormalities among survivors,[2,6,27,28] as a significant proportion of exposed patients with an abnormal echocardiogram at a single visit may be misclassified as cases, potentially causing an overestimation of ventricular dysfunction.\n\nThe clinical significance of asymptomatic echocardiographic abnormalities detected in survivors is often uncertain. Much of the assumed benefit of early detection and treatment are inferred from studies of elderly patients with complex cardiac pathology and additional comorbidities.[29–31] It seems possible, however, that many of the echocardiographic abnormalities detected in survivors are of no clear short-term clinical consequence, as with a median follow-up of 15.8 years, only 4.8% of the cohort ultimately required a pharmaceutical intervention. Similarly, a comparison of studies that report the rate of asymptomatic echocardiographic abnormalities to others reporting clinically apparent heart disease reveals the latter to be considerably less common.[32–38] This suggests that improving the value of screening will require increasing the positive-predictive value of the tests employed, and not simply identifying increasingly subtle abnormalities. Large collaborative case-control studies will likely be required evaluating alternative diagnostic tools, possibly in conjunction with assessment of cardiac biomarkers to develop screening protocols that are capable of identifying precursors of significant heart disease.[39,40]\n\nThis study has several limitations that should be considered. First, although the intent was to evaluate echocardiography based on the COG guidelines, irregular attendance among some patients meant that many underwent echocardiograms at inconsistent time intervals. This likely resulted in some delay in detecting cases that would have been considered “events” earlier had an echocardiogram been performed at a scheduled time. We addressed this issue statistically by performing a series of interval regression analyses to account for inconsistent screening schedules. Secondly, we did not distinguish different types of abnormalities in our analyses separately, and some features of ventricular remodeling (e.g., left ventricular posterior wall dimension) were not always specifically reported. Patients with normal ejection fraction may have other more subtle myocardial changes of uncertain clinical significance, and our study did not routinely capture these.[41] Finally, although patients with persistent or clinically significant echocardiographic abnormalities were referred to tertiary care cardiologists with survivorship experience, there was no formalized protocol for treatment. This reflects the lack of data regarding the optimal management for asymptomatic echocardiographic abnormalities for these survivors. Recognizing these issues, we believe our results reflect the likely outcomes of screening in a specialized follow-up care setting, given the inevitable variation in patient attendance and current uncertainty regarding the best echocardiographic parameter to identify clinically important ventricular dysfunction among survivors. We also did not identify RT as a risk factor for developing echocardiographic abnormalities, likely due to the fact that the median RT dose to our patients was low, and RT-associated valvular abnormalities typically occur >20 years after exposure, which is later than the follow-up of most of the patients on this study. Our results would likely not apply to patients with cardiac doses >15 Gy. Further follow-up among patients with higher RT doses would likely reveal the emergence of valvular abnormalities in some patients.\n\nCONCLUSIONS\nChildhood cancer survivors exposed to ≥250 mg/m2 of anthracyclines prior to age 5 had an ongoing risk of developing sustained echocardiographic abnormalities for up to 25 years following treatment. In contrast, patients receiving <250 mg/m2 after age 5 had no new sustained abnormalities detected after 10 years of follow-up, suggesting that prolonged screening for anthracycline-induced cardiomyopathy could be reconsidered in this group. Efforts should be made to improve not only screening sensitivity, but also the specificity of screening to identify clinically important findings.\n\nThis work was funded by the Canadian Cancer Society through the Pediatric Oncology Group of Ontario. The authors extend their thanks to senior graphic artist, Bruna Ariganello.\n==== Refs\nREFERENCES\n1 Lipshultz SE Cochran TR Franco VI Miller TL Treatment-related cardiotoxicity in survivors of childhood cancer Nat Rev Clin Oncol 2013 12 697 710 24165948 \n2 Abosoudah I Greenberg ML Ness KK Benson L Nathan PC Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors Pediatr Blood Cancer 2011 57 467 472 21280201 \n3 Kremer LCM Mulder RL Oeffinger KC Bhatia S Landier W Levitt G Constine LS Wallace HW Caron HN Armenian SH Skinner R Hudson MM A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: A report from the international late effects of Childhood Cancer Guideline Harmonization Group Pediatr Blood Cancer 2013 60 543 549 23281199 \n4 Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. Children's Oncology Group; 2013. http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf , accessed March 2015 \n5 Wallace W Thompson L Anderson R Long term follow-up of survivors of childhood cancer: Summary of updated SIGN guidance BMJ 2013 346 f1190 23535255 \n6 Hudson MM Rai SN Nunez C Merchant TE Marina NM Zalamea N Cox C Phipps S Pompeu R Rosenthal D Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors J Clin Oncol 2007 25 3635 3643 17704413 \n7 Lipshultz SE Lipsitz SR Sallan SE Dalton VM Mone SM Gelber RD Colan SD Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia J Clin Oncol 2005 23 2629 2636 15837978 \n8 Sorensen K Levitt GA Bull C Dorup I Sullivan ID Late anthracycline cardiotoxicity after childhood cancer Cancer 2003 97 1991 1998 12673729 \n9 Dietz AC Sivanandam S Konety S Kaufman CL Gage RM Kelly AS Neglia JP Mulrooney DA Evaluation of traditional and novel measures of cardiac function to detect anthracycline-induced cardiotoxicity in survivors of childhood cancer J Cancer Surviv 2014 8 183 189 24317971 \n10 Karakurt C Kocak G Ozgen U Evaluation of the left ventricular function with tissue tracking and tissue Doppler echocardiography in pediatric malignancy survivors after anthracycline therapy Echocardiography 2008 25 880 887 18986416 \n11 van der Pal HJ van Dalen EC Hauptmann M Kok WE Caron HN van den Bos C Oldenburger F Koning CC van Leeuwen FE Kremer LC Cardiac function in 5-year survivors of childhood cancer: A long-term follow-up study Arch Intern Med 2010 170 1247 1255 20660845 \n12 Dargie HJ Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial Lancet 2001 357 1385 1390 11356434 \n13 Kober L Torp-Pedersen C Carlsen J Bagger H Eliasen P Lyngborg K Videbaek J Cole DS Auclert L Pauly NC For the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 1995 333 1670 1676 7477219 \n14 Investigators S Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions N Engl J Med 1992 327 685 691 1463530 \n15 Croswell JM Ransohoff DF Kramer BS Principles of cancer screening: Lessons from history and study design issues Semin Oncol 2010 37 202 215 20709205 \n16 Grimes DA Schulz KF Uses and abuses of screening tests Lancet 2002 359 881 884 11897304 \n17 Shankar SM Marina N Hudson MM Adams JM Landier W Bhatia S Meeske K Chen MH Kinahan KE Monitoring for cardiovascular disease in survivors of childhood cancer: Report from the Cardiovascular Disease Task Force of the Children's Oncology Group Pediatrics 2008 121 e387 e396 18187811 \n18 Standards for provision of echocardiography in Ontario. Toronto, ON, Canada: Cardiac Care Network, 2012 \n19 Lang RM Bierig M Devereux RB Flachskampf FA Foster E Pellikka PA Picard MH Roman MJ Seward J Shanewise JS Solomon SD Spencer KT St John Sutton M Stewart WJ Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology J Am Soc Echocardiogr 2005 18 1440 1463 16376782 \n20 Turnbull BW Nonparametric estimation of a survivorship function with doubly censored data J Am Stat Assoc 1974 69 169 173 \n21 R Development Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2013 \n22 Rathe M Carlsen NLT Oxhøj H Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia Pediatr Blood Cancer 2007 48 663 667 17405151 \n23 Andolina JR Dilley K Anthracycline-induced cardiac toxicity more likely in underweight childhood cancer survivors J Pediatr Hematol Oncol 2010 32 411 415 20495481 \n24 Galper SL James BY Mauch PM Strasser JF Silver B LaCasce A Marcus KJ Stevenson MA Chen MH Ng AK Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation Blood 2011 117 412 418 20858859 \n25 Wong FL Bhatia S Landier W Francisco L Leisenring W Hudson MM Armstrong GT Mertens A Stovall M Robison LL Lyman GH Lipshultz SE Armenian SH Cost-effectiveness of the children's oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure Ann Intern Med 2014 160 672 683 24842414 \n26 Yeh JM Nohria A Diller L Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: A model-based estimation of the clinical and economic effects Ann Intern Med 2014 160 661 671 24842413 \n27 Lipshultz SE Landy DC Lopez-Mitnik G Lipsitz SR Hinkle AS Constine LS French CA Rovitelli AM Proukou C Adams JM Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy J Clin Oncol 2012 JCO.2010.2033.7907 \n28 Hequet O Le Q Moullet I Pauli E Salles G Espinouse D Dumontet C Thieblemont C Arnaud P Antal D Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults J Clin Oncol 2004 22 1864 1871 15143078 \n29 Tsang TS Barnes ME Gersh BJ Takemoto Y Rosales AG Bailey KR Seward JB Prediction of risk for first age-related cardiovascular events in an elderly population: The incremental value of echocardiography J Am Coll Cardiol 2003 42 1199 1205 14522480 \n30 Pastore A Geiger S Baur D Hausmann A Tischer J Horster S Stemmler HJ Cardiotoxicity after anthracycline treatment in survivors of adult cancers: Monitoring by USCOM, echocardiography and Serum biomarkers World J Oncol 2013 4 18 25 \n31 Cardinale D Colombo A Lamantia G Colombo N Civelli M De Giacomi G Rubino M Veglia F Fiorentini C Cipolla CM Anthracycline-induced cardiomyopathy clinical relevance and response to pharmacologic therapy J Am Coll Cardiol 2010 55 213 220 20117401 \n32 Vandecruys E Mondelaers V De Wolf D Benoit Y Suys B Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood J Cancer Surviv 2012 6 95 101 21630046 \n33 Mulrooney DA Yeazel MW Kawashima T Mertens AC Mitby P Stovall M Donaldson SS Green DM Sklar CA Robison LL Leisenring WM Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the Childhood Cancer Survivor Study cohort BMJ 2009 339 b4606 19996459 \n34 Termuhlen AM Tersak JM Liu Q Yasui Y Stovall M Weathers R Deutsch M Sklar CA Oeffinger KC Armstrong G Robison LL Green DM Twenty-five year follow-up of childhood Wilms tumor: A report from the Childhood Cancer Survivor Study Pediatr Blood Cancer 2011 57 1210 1216 21384541 \n35 Kremer LC van Dalen EC Offringa M Ottenkamp J Voute PA Anthracycline-induced clinical heart failure in a cohort of 607 children: Long-term follow-up study J Clin Oncol 2001 19 191 196 11134212 \n36 van Dalen EC van der Pal HJ Kok WE Caron HN Kremer LC Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study Eur J Cancer 2006 42 3191 3198 16987655 \n37 Green DM Grigoriev YA Nan B Takashima JR Norkool PA D'Angio GJ Breslow NE Congestive heart failure after treatment for Wilms' tumor: A report from the National Wilms' Tumor Study group J Clin Oncol 2001 19 1926 1934 11283124 \n38 Creutzig U Diekamp S Zimmermann M Reinhardt D Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML Pediatr Blood Cancer 2007 48 651 662 17183582 \n39 Armstrong GT Plana JC Zhang N Srivastava D Green DM Ness KK Donovan FD Metzger ML Arevalo A Durand JB Screening adult survivors of childhood cancer for cardiomyopathy: Comparison of echocardiography and cardiac magnetic resonance imaging J Clin Oncol 2012 30 2876 2884 22802310 \n40 Monsuez JJ Detection and prevention of cardiac complications of cancer chemotherapy Arch Cardiovasc Dis 2012 105 593 604 23177488 \n41 Armenian SH Gehlehter SK Vase T Venkatramani R Landier W Wilson KD Herrera C Reichman L Menteer JD Mascarenhas L Freyer DR Venkataraman K Bhatia S Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors Clin Cancer Res 2014 20 6314 6323 24947931\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1545-5009", "issue": "62(12)", "journal": "Pediatric blood & cancer", "keywords": "anthracycline; cardiotoxicity; pediatric cancer; survivorship", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000328:Adult; D018943:Anthracyclines; D002648:Child; D002675:Child, Preschool; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D017741:Survivors", "nlm_unique_id": "101186624", "other_id": null, "pages": "2197-203", "pmc": null, "pmid": "26146944", "pubdate": "2015-12", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "11134212;11283124;11356434;11897304;12673729;14522480;1463530;15143078;15837978;16376782;16987655;17183582;17405151;17704413;18187811;18986416;19996459;20117401;20495481;20660845;20709205;20858859;21280201;21384541;21630046;22393080;22802310;23177488;23281199;23535255;24165948;24317971;24842413;24842414;24947931;29147326;7477219", "title": "Echocardiographic Detection of Cardiac Dysfunction in 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Echocardiogram abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAMJAUN A, EMAN A, AHMED S, WANG L, YU E, NATHAN PC, ET AL. ECHOCARDIOGRAPHIC DETECTION OF CARDIAC DYSFUNCTION IN CHILDHOOD CANCER SURVIVORS: HOW LONG IS SCREENING REQUIRED?. PEDIATR BLOOD CANCER 2015?62:2197-2203.", "literaturereference_normalized": "echocardiographic detection of cardiac dysfunction in childhood cancer survivors how long is screening required", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151116", "receivedate": "20151116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11742022, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "There is a dearth of prospective trials studying treatment response in Persistent Delusional Disorder (PDD) to guide clinical practice. Available retrospective data indicate good response to second-generation antipsychotics (SGAs). We selected the data of patients prescribed either olanzapine or risperidone from a retrospective chart review of PDD (n=455) at our centre. We compared the two groups olanzapine (n =86) versus risperidone (n =280) on dose, drug adherence, response and adverse effects. The two groups were comparable on socio-demographic and clinical characteristics of PDD. There was no statistically significant difference between the two groups on adherence (>80%) and response to treatment (>52% good response). Olanzapine was effective at lower mean chlorpromazine equivalents than risperidone. Logistic regression analysis identified shorter mean duration of illness, good adherence and absence of substance dependence as predictors of good response to both drugs. Our study indicates that acute PDD responds well to treatment with both risperidone and olanzapine, provided adherence can be ensured. In the absence of specific treatment guidelines and randomized controlled trials for PDD, our analysis reaffirms the efficacy of SGAs.", "affiliations": "Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Consultant Psychiatrist, Epworth Hospital, Camberwell, Victoria - 3124 & Honorary Consultant, Department of Psychiatry, Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne, Australia.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Biostatistics, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India. Electronic address: [email protected].", "authors": "Kulkarni\|Karishma\|K\|;Arasappa\|Rashmi\|R\|;Prasad M\|Krishna\|K\|;Zutshi\|Amit\|A\|;Chand\|Prabhat K\|PK\|;Murthy\|Pratima\|P\|;Philip\|Mariamma\|M\|;Muralidharan\|Kesavan\|K\|", "chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine; D002746:Chlorpromazine", "country": "Ireland", "delete": false, "doi": "10.1016/j.psychres.2017.02.066", "fulltext": null, "fulltext_license": null, "issn_linking": "0165-1781", "issue": "253()", "journal": "Psychiatry research", "keywords": "Chlorpromazine equivalents; Logistic regression; Predictors of response; Second generation antipsychotics; Treatment response", "medline_ta": "Psychiatry Res", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002746:Chlorpromazine; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011446:Prospective Studies; D012189:Retrospective Studies; D018967:Risperidone; D012563:Schizophrenia, Paranoid; D016896:Treatment Outcome", "nlm_unique_id": "7911385", "other_id": null, "pages": "270-273", "pmc": null, "pmid": "28411574", "pubdate": "2017-07", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Risperidone versus olanzapine in the acute treatment of Persistent Delusional Disorder: A retrospective analysis.", "title_normalized": "risperidone versus olanzapine in the acute treatment of persistent delusional disorder a retrospective analysis" }	[ { "companynumb": "IN-JNJFOC-20170503763", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "MEAN DOSE: 4.9 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DELUSIONAL DISORDER, UNSPECIFIED TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "MEAN DOSE: 4.9 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSIVE SYMPTOM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tardive dyskinesia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hospitalisation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle rigidity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Salivary hypersecretion", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse reaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KULKARNI K, ARASAPPA R, PRASAD MK, ZUTSHI A, CHAND PK, MURTHY P, ET AL. RISPERIDONE VERSUS OLANZAPINE IN THE ACUTE TREATMENT OF PERSISTENT DELUSIONAL DISORDER: A RETROSPECTIVE ANALYSIS. PSYCHIATRY RESEARCH 2017?253:270-273. KULKARNI K, ARASAPPA R, PRASAD MK, ZUTSHI A, CHAND PK, MURALIDHARAN K, ET AL. THE IMPACT OF DEPRESSIVE SYMPTOMS ON THE CLINICAL PRESENTATION OF PERSISTENT DELUSIONAL DISORDER. ASIAN JOURNAL OF PSYCHIATRY 2018?32:123-125.", "literaturereference_normalized": "risperidone versus olanzapine in the acute treatment of persistent delusional disorder a retrospective analysis", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20180109", "receivedate": "20170508", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13524256, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" } ]
{ "abstract": "The sting from Centuroides sculpturatus, commonly known as the bark scorpion, is a serious medical problem and can be potentially fatal to young children. Centuroides sculpturatus envenomation can cause a wide spectrum of symptoms, often including autonomic dysfunction, cranial nerve abnormalities, and somatic motor abnormalities. We discuss a 6-month-old male infant who presented with signs and symptoms consistent with bark scorpion envenomation, later found to be secondary to methamphetamine toxicity. Emergency pediatricians should be aware of the strong similarities between scorpion envenomation and methamphetamine toxicity in pediatric patients residing in or having visited the southwestern region of the United States. Methamphetamine toxicity should be considered in their differential diagnosis.", "affiliations": "From the Department of Pediatrics, University of Arizona, Tucson, AZ.", "authors": "Pariury\|Holly E\|HE\|;Steiniger\|Aimee M\|AM\|;Lowe\|Merlin C\|MC\|", "chemical_list": "D000997:Antivenins; D000697:Central Nervous System Stimulants; D012604:Scorpion Venoms; D008694:Methamphetamine", "country": "United States", "delete": false, "doi": "10.1097/PEC.0000000000001301", "fulltext": null, "fulltext_license": null, "issn_linking": "0749-5161", "issue": "33(11)", "journal": "Pediatric emergency care", "keywords": null, "medline_ta": "Pediatr Emerg Care", "mesh_terms": "D000818:Animals; D000997:Antivenins; D000697:Central Nervous System Stimulants; D003937:Diagnosis, Differential; D006801:Humans; D007223:Infant; D008297:Male; D008694:Methamphetamine; D065008:Scorpion Stings; D012604:Scorpion Venoms; D012605:Scorpions", "nlm_unique_id": "8507560", "other_id": null, "pages": "e124-e125", "pmc": null, "pmid": "29095780", "pubdate": "2017-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Stinging Suspicion Something Was Just Not Right: Methamphetamine Toxicity in Infant Mimics Scorpion Envenomation.", "title_normalized": "a stinging suspicion something was just not right methamphetamine toxicity in infant mimics scorpion envenomation" }	[ { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-05301", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203846", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Eye movement disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Restlessness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Depressed mood", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Irritability", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PARIURY H,STEINIGER A,LOWE M. A STINGING SUSPICION SOMETHING WAS JUST NOT RIGHT METHAMPHETAMINE TOXICITY IN INFANT MIMICS SCORPION ENVENOMATION. PEDIATRIC EMERGENCY CARE 2017?33(11):124-125.", "literaturereference_normalized": "a stinging suspicion something was just not right methamphetamine toxicity in infant mimics scorpion envenomation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180123", "receivedate": "20180104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14349148, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "US-RECORDATI RARE DISEASES-US-R13005-17-00242", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "005378", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pupillary disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Irritability", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Movement disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PARIURY H,STEINIGER A,LOWE M. A STINGING SUSPICION SOMETHING WAS JUST NOT RIGHT: METHAMPHETAMINE TOXICITY IN INFANT MIMICS SCORPION ENVENOMATION. PEDIATRIC EMERGENCY CARE 2017 NOV;33(11):E124-E125.", "literaturereference_normalized": "a stinging suspicion something was just not right methamphetamine toxicity in infant mimics scorpion envenomation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171117", "receivedate": "20171117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14198125, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]
{ "abstract": "BACKGROUND\nSerotonin syndrome is a potentially fatal complication that usually occurs in the combination use of several serotonergic agents. We presented a patient with major depressive disorder under the treatment of bupropion, trazodone, and quetiapine. Serotonin syndrome developed soon after she received the first session of electroconvulsive therapy (ECT).\n\n\nMETHODS\nThis study is a case report.\n\n\nRESULTS\nA 70-year-old female with major depressive disorder developed serotonin syndrome after the first session of ECT in combination with bupropion, trazodone, and quetiapine. Serotonin syndrome did not reappear in the subsequent ECT treatment while in the treatment with different therapeutic agents.\n\n\nCONCLUSIONS\nThe superimposing effect of ECT in conjunction with serotonergic agents might contribute to the development of serotonin syndrome.", "affiliations": "*Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital; and †Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.", "authors": "Cheng\|Ying-Chih\|YC\|;Liang\|Chun-Mao\|CM\|;Liu\|Hsing-Cheng\|HC\|", "chemical_list": "D017367:Serotonin Uptake Inhibitors; D016642:Bupropion; D000069348:Quetiapine Fumarate; D014196:Trazodone", "country": "United States", "delete": false, "doi": "10.1097/WNF.0000000000000076", "fulltext": null, "fulltext_license": null, "issn_linking": "0362-5664", "issue": "38(3)", "journal": "Clinical neuropharmacology", "keywords": null, "medline_ta": "Clin Neuropharmacol", "mesh_terms": "D000368:Aged; D016642:Bupropion; D003131:Combined Modality Therapy; D003865:Depressive Disorder, Major; D004359:Drug Therapy, Combination; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D000069348:Quetiapine Fumarate; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D014196:Trazodone; D016896:Treatment Outcome", "nlm_unique_id": "7607910", "other_id": null, "pages": "112-3", "pmc": null, "pmid": "25970280", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Serotonin syndrome after electroconvulsive therapy in a patient on trazodone, bupropion, and quetiapine: a case report.", "title_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report" }	[ { "companynumb": "TW-MYLANLABS-2015M1022189", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y-C, LIANG C-M, LIU H-C. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN-NEUROPHARMACOL 2015? 38(3):112-113.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160309", "receivedate": "20150707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11243384, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160525" }, { "companynumb": "TW-WATSON-2016-08690", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "070857", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE HYDROCHLORIDE (WATSON LABORATORIES)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "005", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE (ACTAVIS LABORATORIES FL)" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE (UNKNOWN)" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "070857", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE HYDROCHLORIDE (WATSON LABORATORIES)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "150 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE (ACTAVIS LABORATORIES FL)" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Potentiating drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG YC, LIANG CM, LIU HC. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN NEUROPHARMACOL. 2015;38(3):112-3.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160504", "receivedate": "20160504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12332968, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-099814", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y-C, LIANG C-M, LIU H-C. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN-NEUROPHARMACOL. 2015;38(3):112-113", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150820", "receivedate": "20150707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11242896, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "PHHY2015TW077701", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN 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INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Body temperature increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somatic delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorganised speech", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscle rigidity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y-C, LIANG C-M, LIU H-C.. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT.. CLIN-NEUROPHARMACOL. 2015;38(3):112-113", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150706", "receivedate": "20150706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11240196, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "TW-ACCORD-031021", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PROPOFOL ANESTHESIA", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLLY RECEIVED 50 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": [ { "drugrecuraction": "Serotonin syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202152", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLY RECEIVED 200 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Serotonin syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLLY RECEIVED 150 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Serotonin syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION/BUPROPION HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG YC, LIANG CM, LIU HC. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN NEUROPHARMACOL. 2015 MAY-JUN;38(3):112-3.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150527", "receivedate": "20150527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11138699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "TW-ROXANE LABORATORIES, INC.-2015-RO-01219RO", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y,LIANG C,LIU H. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLINICAL NEUROPHARMACOLOGY 2015 MAY;38:3:112-113.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "TW", "receiptdate": "20150729", "receivedate": "20150729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11321472, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "TW-ALKEM-001016", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLLY RECEIVED 150 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Serotonin syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION/BUPROPION HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLLY RECEIVED 50 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": [ { "drugrecuraction": "Serotonin syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PROPOFOL ANESTHESIA", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "201504", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLY RECEIVED 200 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Serotonin syndrome" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE/QUETIAPINE FUMARATE" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG YC, LIANG CM, LIU HC. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN NEUROPHARMACOL. 2015 MAY-JUN;38(3):112-3.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150528", "receivedate": "20150528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11143780, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]
{ "abstract": "Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids.", "affiliations": "Department of Respirology, Graduate School of Medicine, Chiba University, Japan.", "authors": "Kasai\|Hajime\|H\|;Terada\|Jiro\|J\|;Hoshi\|Hiromasa\|H\|;Urushibara\|Takashi\|T\|;Kato\|Fumiaki\|F\|;Nishimura\|Rintaro\|R\|;Tatsumi\|Koichiro\|K\|", "chemical_list": "D005938:Glucocorticoids", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.56.7614", "fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7614Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28202865Case ReportRepeated Diffuse Alveolar Hemorrhage in a Patient with Hemophilia B Kasai Hajime 1Terada Jiro 1Hoshi Hiromasa 2Urushibara Takashi 1Kato Fumiaki 1Nishimura Rintaro 1Tatsumi Koichiro 11 Department of Respirology, Graduate School of Medicine, Chiba University, Japan2 Department of Medicine, School of Medicine, Chiba University, JapanCorrespondence to Dr.　Hajime Kasai, [email protected]\n\n15 2 2017 56 4 425 428 21 4 2016 14 6 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids. \n\ndiffuse alveolar hemorrhagehemophiliacorticosteroid\n==== Body\nIntroduction\nDiffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of various clinical entities such as connective tissue disease and a small vessel vasculitis (pulmonary capillaritis); it may also be caused by coagulation disorders (1). Hemophilia, which is a recessive, X-linked congenital bleeding disorder, has rarely been reported in association with DAH. Bleeding in patients with hemophilia mostly occurs internally into the joints or muscles (2). Refractory bleeding after invasive procedures or trauma is a major reason to suspect hemophilia. Although hemophilia is usually diagnosed in adolescence, mild or moderate hemophilia may sometimes escape detection until adulthood (3,4). We herein present the case of a patient with recurrent DAH who was diagnosed with hemophilia B in adulthood.\n\nCase Report\nThe patient was a 48-year-old man who had previously been hospitalized due to hemoptysis at 42 years of age. At that time, a chest radiograph and chest computed tomography (CT) revealed diffuse ground-glass opacity (GGO) in the bilateral lung fields (Fig. 1, 2), and a bronchoscopic examination revealed the accumulation of large amounts of blood in the trachea and bronchi (Fig. 3). The patient's bronchoalveolar lavage fluid (BALF) was bloody and contained numerous hemosiderin-laden macrophages. A culture test of the BALF revealed no findings. An electrocardiogram and transthoracic echocardiogram revealed no abnormalities. A questionnaire that was completed at that time did not reveal the patient's hemorrhagic episode or a family history of bleeding disease, with the exception of his younger brother who had been diagnosed with hepatitis C. Furthermore, he had not received any drugs that had the potential to cause DAH. Following the above-mentioned examinations, DAH due to some sort of vasculitis was suspected. Thus, treatment with high-dose intravenous methylprednisolone (1,000 mg daily) for 3 days followed by prednisolone (25 mg daily) was initiated. This relieved his symptoms. Chest CT showed the resolution of the GGO. The patient's prednisolone dose was tapered and eventually discontinued at two-and-a-half years after his discharge from our hospital.\n\nFigure 1. A chest radiograph at the time of the first admission showed the presence of diffuse ground-glass opacity in the bilateral lung fields.\n\nFigure 2. Chest computed tomography at the time of the first admission showed diffuse ground-glass opacity in the bilateral lung fields.\n\n\nFigure 3. A bronchoscopic examination at the time of the first admission showed the accumulation of a large amount of blood in the trachea and bronchi.\n\n\nThe patient was readmitted to our hospital with a recurrence of hemoptysis at 46 years of age. The above-described therapy was initiated and led to the improvement of his condition. The prednisolone dose was tapered from 60 mg daily to a maintenance dose of 5 mg daily.\n\nAt 48 years of age, he was readmitted to our hospital with a further recurrence of hemoptysis. At this point, he had steroid-induced diabetes mellitus, which was treated with glimepiride (3 mg daily). At admission, his weight was 75 kg and height 167 cm; his vital signs were as follows: blood pressure, 178/102 mmHg; pulse rate, 109 beats/min, pulse oximetry, 97% in room air; and body temperature, 36.8°C. Chest auscultation revealed fine crackles in the right lung field. No skin rash, subcutaneous bleeding or joint swelling were present. A chest radiograph and CT showed the presence of diffuse GGO in the bilateral lung fields. Mild anemia was observed (hemoglobin, 11.3 g/dL), although hemoglobin levels had been 14.6 g/dL prior to the hemoptysis episode. The activated partial thromboplastin time (APTT) was prolonged to 53.5 seconds (normal range, 25.1-40.7 seconds). Laboratory tests showed that the patient's blood glucose and hemoglobin A1c levels were 299 mg/dL and 8.2%, respectively, due to the steroid-induced diabetes mellitus. Autoantibodies for various collagen diseases were negative (Table). We diagnosed the condition as a recurrence of DAH and again administered high-dose intravenous methylprednisolone for 3 days, followed by prednisolone (60 mg daily). His condition improved, as had been observed during the previous episodes. A further detailed inquiry regarding the patient's medical history revealed that, as an elementary school student, he had been hospitalized and had received blood transfusions twice following abnormally heavy bleeding after tooth extraction; however, a specific congenital bleeding disorder had not been diagnosed at that time. It was also revealed that his younger brother had been diagnosed with hemophilia B during adolescence. Considering the possibility of hemophilia, his blood coagulation factors were examined, revealing that his factor IX activity was 3%. The patient was subsequently diagnosed with moderate hemophilia B. By the time of this diagnosis, the patient's DAH had already resolved with the corticosteroid therapy. We decided to continue treating the patient using prednisolone alone, without coagulation factor IX replacement therapy. No recurrence of DAH or hemorrhagic symptoms have been observed during 3 years since the tapering and discontinuation of prednisolone.\n\nTable. Laboratory Data on Admission.\n\nComplete blood count\t\t\tBlood chemistry\t\t\tImmunology\t\t\t\nWBC\t11,400\t/µL\tAST\t30\tU/L\tCRP\t1.3\tmg/dL\t\nNeutrophil\t72.3\t%\tALT\t61\tU/L\tRheumatoid factor\t<5\tunits\t\nEosinophil\t10.7\t%\tLDH\t318\tU/L\tAnti-RNA antibody\tnegative\t\t\nMonocyte\t5.2\t%\tALP\t196\tU/L\tAnti-SS-A/Ro antibody\tnegative\t\t\nLymphocyte\t11.6\t%\tγ-GTP\t113\tU/L\tAnti-SS-B/Ro antibody\tnegative\t\t\nRBC\t411×104\t/µL\tTP\t7\tg/dL\tAnti-centromere antibody\tnegative\t\t\nHGB\t11.3\tg/dL\tALB\t4.3\tg/dL\tAnti-Jo1 antibody\tnegative\t\t\nHCT\t34.5\t%\tUA\t3.9\tmg/dL\tAnti-smith antibody\tnegative\t\t\nPLT\t26.3×104\t/µL\tUN\t13\tmg/dL\tAnti-topoisomerase I antibody\tnegative\t\t\n\t\t\tCRE\t0.73\tmg/dL\tPR3-ANCA\t<10\tEU\t\nCoagulation system\t\t\tT-BIL\t1.1\tmg/dL\tMPO-ANCA\t<10\tEU\t\nAPTT\t53.5\tsec\tID-BIL\t0.1\tmg/dL\tAnti-GBM antibody\t<10\tEU\t\nPT\t11.4\tsec\tNa\t139\tmmol/L\tDouble standard DNA antibody\t<10\tIU/mL\t\nPT activity\t87\t%\tK\t3.7\tmmol/L\tCardiolipin antibody\t<8\tU/mL\t\nPT-INR\t1.03\t\tCl\t104\tmmol/L\t\t\t\t\n\t\t\tGlucose\t299\tmg/dL\tUrine test\t\t\t\n\t\t\tHbA1c\t8.2\t%\tWhite blood cell count\t<1\tHPF\t\n\t\t\t\t\t\tRed blood cell count\t<1\tHPF\t\n\t\t\t\t\t\tUrinary sugar\t4+(1,000)\t\t\nAPTT: activated partial thromboplastin, PT: prothrombin time, PT-INR: PT international normalized ratio, PR3-ANCA: proteinase 3 antineutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-antineutrophil cytoplasmic antibody, GBM: glomerular basement membrane, HPF: high power field\n\nDiscussion\nThe present case raises two clinical issues. First, hemophilia can be associated with repeated DAH and may act as an exacerbating factor. Second, in cases with serious bleeding events, such as DAH in the present case, hemophilia may be overlooked in adolescent patients.\n\nCongenital coagulation disorders, including hemophilia, are known to be the rare causes of DAH (1). In general clinical settings, DAH is mainly caused by pulmonary capillaritis in association with systemic autoimmune diseases, pulmonary renal syndromes, and drugs (5,6). In such cases, treatment with corticosteroids and immunosuppressive agents is often effective. In the present case, the patient's DAH was likely associated with pulmonary capillaritis as it resolved quickly after the initiation of corticosteroid therapy. However, different subtypes of DAH, such as coagulation disorder, mitral stenosis, and acute respiratory distress syndrome, are known to be refractory to corticosteroids and/or immunosuppressive agents. Thus, a careful evaluation is needed in selecting an appropriate treatment for patients with DAH.\n\nSpontaneous hemoptysis as a rare manifestation of DAH in patients with a congenital coagulation disorder. There have only been nine reported cases of hemoptysis occurring with hemophilia; in six of these cases the patients had a concurrent infection (3,7-12). There have been no reports about the frequency of DAH in patients with hemophilia. Although the exact frequency is not known, it is expected to be extremely low. These results suggest that coagulation defectsgenerally play a secondary role in pulmonary hemorrhage and are not a primary cause (8). The occurrence of hemoptysis in patients with hemophilia and other bleeding disorders may therefore indicate the existence of an associated underlying disease (8).\n\nIn the present case, the underlying disease was considered to be some sort of pulmonary capillaritis, with hemophilia B being conducive to bleeding. Corticosteroids are not effective when DAH is caused by hemophilia alone. Hemophilia treatment (other than corticosteroids) was considered for the patient in the present case. Generally, such treatments are determined by the severity of hemophilia, which is classified according to coagulation factor levels as severe (<1%), moderate (1-5%), or mild (5-40%) (13). In cases of moderate hemophilia B, factor IX products are generally replaced at the time that the symptoms appear. In the present case, we continued to treat the patient with prednisolone alone after the second recurrence of DAH, because his hemoptysis had already disappeared in response to corticosteroid therapy at the time of the diagnosis of hemophilia and because the patient's diabetes mellitus and hypertension were controllable with the adjustment of oral hypoglycemic and antihypertensive medications. However, the patient's DAH recurred despite the provision of corticosteroid therapy, this treatment alone may not have been sufficient to achieve the long-term control of DAH. Thus, if it is not possible to control DAH or if other complications such as diabetes mellitus arise due to the corticosteroid therapy, as occurred in the present case, coagulation factor IX replacement therapy is required.\n\nIn the present case, at the time of the first admission, the patient did not recognize that his bleeding episodes were hemorrhagic, and our questioning at the time did not reveal the blood transfusion episodes during his childhood or his brother's medical history. The presence of a mild extended APTT also left us unaware that the patient's condition was complicated with hemophilia. Furthermore, because he showed quite a good response to corticosteroids, we considered pulmonary capillaritis to have been the cause of DAH. Because further inquiries were not, even at the time of first recurrence of DAH, the diagnosis of hemophilia B was delayed. Matsumoto et al. reported the case of an 18-year-old patient with hemophilia B who had tuberculosis with non-cavitary lung disease. He had not been diagnosed in adolescence and presented with recurring hemoptysis (3). They further reported that hemophilia A often escapes detection, even in patients with factor VIII levels as high as 25%, until a heavy bleeding episode after major trauma or surgery (3). These results underscore the importance of performing a repeated, detailed inquiry regarding congenital bleeding diseases, even if DAH shows good response to corticosteroids.\n\nWe herein presented a case in which a patient was diagnosed with hemophilia B after repeated recurrences of DAH. There may be other cases of hemophilia that remain undiagnosed until adulthood. Attention should be paid to the possibility of hemophilia, even in adult patients with an unexplained recurrence of DAH.\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\nKoichiro Tatsumi: Honoraria, GlaxoSmithKline and Pfizer.\n\nKoichiro Tatsumi Research funding, The Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare, Japan.\n==== Refs\n1. Lara AR , Schwarz MI \nDiffuse alveolar hemorrhage . Chest \n137 : 1164 -1171 , 2010 .20442117 \n2. Srivastava A , Brewer AK , Mauser-Bunschoten EP , et al \nGuidelines for the management of hemophilia . Haemophilia \n19 : e1 -e47 , 2013 .22776238 \n3. Matsumoto H , Suzuki K , Watanabe I , et al \nRecurrent hemoptysis in tuberculosis with non-cavitary lung disease as a symptom of mild hemophilia A in a young adult . Intern Med \n39 : 63 -65 , 2000 .10674852 \n4. Peyvandi F , Garagiola I , Young G \nThe past and future of haemophilia: diagnosis, treatments, and its complications . Lancet \n388 : 187 -197 , 2016 .26897598 \n5. Newsome BR , Morales JE \nDiffuse alveolar hemorrhage . South Med J \n104 : 269 -274 , 2011 .21606695 \n6. Specks U \nDiffuse alveolar hemorrhage syndromes . Curr Opin Rheumatol \n13 : 12 -17 , 2001 .11148710 \n7. Suzuki T , Yamamoto Y , Otaki M , et al \nAcute alveolar haemorrhage in a patient with haemophilia B . Haemophilia \n18 : e29 -e31 , 2012 .22004358 \n8. Girolami A , Vettore S , Scandellari R , Allemand E , Girolami B \nAbout the rarity of haemoptysis in congenital bleeding disorders. A report of five cases . Haemophilia \n15 : 825 -827 , 2009 .19444978 \n9. Connolly JP \nHemoptysis as a presentation of mild hemophilia A in an adult . Chest \n103 : 1281 -1282 , 1993 .8131487 \n10. Takeda R , Mabuchi H \nA massive pulmonary hemorrhage resulting in cavitation occurring in a case of hemophilia A associated with diabetes mellitus . South Med J \n67 : 869 -873 , 1974 .4834749 \n11. O'Dwyer ME , DeLoughery TG \nPulmonary hemorrhage in a hemophiliac simulating a lung neoplasm . Am J Hematol \n64 : 299 -302 , 2000 .10911383 \n12. Chandrakala S , Jijina F , Ghosh K \nDiffuse alveolar haemorrhage with severe haemophilia . Haemophilia \n16 : 962 -964 , 2010 .20491960 \n13. White GC 2nd, Rosendaal F , Aledort LM , et al \nDefinitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis . Thromb Haemost \n85 : 560 , 2001 .11307831\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(4)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": null, "medline_ta": "Intern Med", "mesh_terms": "D001999:Bronchoscopy; D005938:Glucocorticoids; D002836:Hemophilia B; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "9204241", "other_id": null, "pages": "425-428", "pmc": null, "pmid": "28202865", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10674852;11307831;21606695;19444978;20491960;8131487;10911383;11148710;20442117;22004358;26897598;4834749;22776238", "title": "Repeated Diffuse Alveolar Hemorrhage in a Patient with Hemophilia B.", "title_normalized": "repeated diffuse alveolar hemorrhage in a patient with hemophilia b" }	[ { "companynumb": 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{ "abstract": "Anti-tumor necrosis factor (TNF)-α therapy is established as a new standard for the treatment of various autoimmune inflammatory diseases. We report the first case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF-α therapy. A 56-year-old man with Crohn's disease presented with fever and a diffuse, tender goiter. To control the diarrhea, anti-TNF therapy (infliximab) was administered 4 weeks before the thyroid symptoms emerged. The patient reported a swollen neck with tenderness on the right side and fever 4 days after the second infliximab injection. An elevated serum C-reactive protein (CRP) and serum thyroid hormone level with suppressed serum thyrotropin were observed. The thyroid-stimulating antibody was not elevated. An ultrasonograph of the thyroid revealed an enlarged goiter with posterior echogenicity attenuation and a low echoic region that was tender. The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range. The patient was initially diagnosed with thyrotoxicosis resulting from subacute thyroiditis. Administration of oral prednisolone improved the fever, thyroid pain, and thyroid function, but his thyroid remained swollen. The patient developed diarrhea after prednisolone withdrawal; therefore, adalimumab, another TNF inhibitor, was administered. After three injections, his abdominal symptoms were alleviated, but the thyroid pain and fever recurred. Elevated serum CRP levels in the absence of thyroid dysfunction were observed. The patient's symptoms resolved after prednisolone retreatment, but an elastic, firm goiter persisted. A fine-needle biopsy revealed amyloid deposition in the thyroid.\n\n\nCONCLUSIONS\nMany cases with thyroid dysfunction accompanied by amyloid goiter have been reported.There are cases that develop amyloid goiter with subacute thyroiditis-like symptoms after anti-TNF therapy.When the thyroid remains swollen after improvement of thyrotoxicosis following treatment with prednisolone, it should be assessed to differentiate between an amyloid goiter and common subacute thyroiditis.", "affiliations": "Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.;Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.;Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.;Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.", "authors": "Kawashima\|Junji\|J\|;Naoe\|Hideaki\|H\|;Sasaki\|Yutaka\|Y\|;Araki\|Eiichi\|E\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1530/EDM-14-0117", "fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepedmEDM Case ReportsEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 25969738EDM14011710.1530/EDM-14-0117Unique/Unexpected Symptoms or Presentations of a DiseaseA rare case showing subacute thyroiditis-like symptoms with amyloid goiter after anti-tumor necrosis factor therapy Subacute thyroiditis-like symptoms with amyloid goiterKawashima Junji 1Naoe Hideaki 2Sasaki Yutaka 2Araki Eiichi 11 Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan2 Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, JapanCorrespondence should be addressed to J Kawashima Email: [email protected] 5 2015 2015 2015 1401171 4 2015 8 4 2015 © 2015 The authors2015This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nAnti-tumor necrosis factor (TNF)-α therapy is established as a new standard for the treatment of various autoimmune inflammatory diseases. We report the first case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF-α therapy. A 56-year-old man with Crohn's disease presented with fever and a diffuse, tender goiter. To control the diarrhea, anti-TNF therapy (infliximab) was administered 4 weeks before the thyroid symptoms emerged. The patient reported a swollen neck with tenderness on the right side and fever 4 days after the second infliximab injection. An elevated serum C-reactive protein (CRP) and serum thyroid hormone level with suppressed serum thyrotropin were observed. The thyroid-stimulating antibody was not elevated. An ultrasonograph of the thyroid revealed an enlarged goiter with posterior echogenicity attenuation and a low echoic region that was tender. The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range. The patient was initially diagnosed with thyrotoxicosis resulting from subacute thyroiditis. Administration of oral prednisolone improved the fever, thyroid pain, and thyroid function, but his thyroid remained swollen. The patient developed diarrhea after prednisolone withdrawal; therefore, adalimumab, another TNF inhibitor, was administered. After three injections, his abdominal symptoms were alleviated, but the thyroid pain and fever recurred. Elevated serum CRP levels in the absence of thyroid dysfunction were observed. The patient's symptoms resolved after prednisolone retreatment, but an elastic, firm goiter persisted. A fine-needle biopsy revealed amyloid deposition in the thyroid.\n\nLearning points\n\nMany cases with thyroid dysfunction accompanied by amyloid goiter have been reported.\n\nThere are cases that develop amyloid goiter with subacute thyroiditis-like symptoms after anti-TNF therapy.\n\nWhen the thyroid remains swollen after improvement of thyrotoxicosis following treatment with prednisolone, it should be assessed to differentiate between an amyloid goiter and common subacute thyroiditis.\n==== Body\nBackground\nThyroid dysfunction resulting from therapeutic pharmacological agents is often encountered in clinical practice. Various medicines, such as amiodarone and interferon-α, have been reported to induce thyrotoxicosis (1). Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of numerous inflammatory conditions, and its inhibition has proven efficacious in the treatment of autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Recently, several cases of thyrotoxicosis have been reported in association with anti-TNF therapy using etanercept (2)\n(3)\n(4)\n(5). However, thyrotoxicosis accompanied by an amyloid goiter after anti-TNF therapy has never been reported.\n\nIn the present report, we present the first reported case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF therapy for Crohn's disease.\n\nCase presentation\nA 56-year-old man who had been suffering from diarrhea since the age of 50 was diagnosed with Crohn's disease. He had no previous history of a thyroid disease or the use of other medications known to induce thyroid dysfunction. He had no history of neck pain, irradiation, or recent fever and no family history of thyroid disease. At the age of 56 years, he was treated with the TNF inhibitor infliximab (5 mg/kg) on April 26, 2012, and May 9, 2012, to improve diarrhea. He noticed neck swelling with right neck tenderness and fever 4 days after the second injection of infliximab and thus was referred to our department on May 23, 2012.\n\nPhysical examination revealed that he was undernourished, with a height of 1.67 m and a weight of 52.0 kg. His body temperature was 36.5 °C because had been taking acetaminophen since May 13, 2012. His blood pressure was 154/80 mmHg, and his pulse was 71 bpm. He did not have lid retraction, hyperhidrosis, or tremor of the fingers. An elastic, firm goiter was palpable, primarily in the right lobe of the thyroid, which was tender.\n\nInvestigation\nThe laboratory data revealed hypochromic anemia, hypoalbuminemia, and hypolipidemia (Table 1). His renal function was normal, with the exception of a slightly elevated urinary protein level. His serum C-reactive protein (CRP) was elevated, whereas his white blood cell count was within normal range. His serum free triiodothyronine (fT3) and serum free thyroxine (fT4) were both elevated, and his serum thyroid stimulating hormone (TSH) was low. His serum thyroglobulin (Tg) was elevated, and anti-Tg and anti-thyroid peroxidase antibodies were absent. Thyroid-stimulating antibodies were not elevated. Ultrasonography of his thyroid gland revealed an enlarged goiter (estimated thyroid volume: 46.8 ml), particularly in the right lobe, with irregular hypoechoic region in the right lobe and posterior attenuation of echogenicity (Fig. 1). The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range (Fig. 2). Thus, his condition at that time was diagnosed as thyrotoxicosis resulting from subacute thyroiditis but not from Graves’ disease.\n\nTable 1 Laboratory results (May 23, 2012). Values presented in italics are below the normal lower limit, whereas those in bold are above the normal upper limit. Tg-antibody and TPO-antibody were measured by the electrochemiluminescence (ECLIA) method\n\n\nLaboratory tests\n\t\nPatient's values\n\t\nReference range\n\t\nWBC (/mm3)\t4200\t(3500–8500)\t\n Neut. (%)\t70.0\t(40.7–74.8)\t\n Lymp. (%)\t18.5\t(19.0–49.7)\t\n Mono. (%)\t7.2\t(1.0–9.0)\t\n Eosin. (%)\t4.1\t(0–6.6)\t\nRBC (×106 μl)\t3.38\t(4.31–5.65)\t\nHemoglobin (g/dl)\t9.8\t(14.0–17.7)\t\nHematocrit (%)\t29.8\t(40.4–50.8)\t\nPlatelet (/mm3)\t243\t(145–325)\t\nTotal protein (g/dl)\t7.3\t(6.5–8.3)\t\nAlbumin (g/dl)\t3.8\t(3.9–4.9)\t\nNa (mEq/l)\t144\t(138–146)\t\nK (mEq/l)\t3.9\t(3.5–5.0)\t\nCl (mEq/l)\t110\t(99–109)\t\nCa (mg/dl)\t9.5\t(8.3–10.5)\t\nP (mg/dl)\t3.3\t(2.5–4.8)\t\nBUN (mg/dl)\t20.9\t(8–24)\t\nCreatinine (mg/dl)\t0.95\t(0.56–1.18)\t\nAST (U/l)\t30\t(13–34)\t\nALT (U/l)\t31\t(7–37)\t\nγ-GTP (U/l)\t21\t(9–47)\t\nLDH (U/l)\t167\t(112–213)\t\nALP (U/l)\t239\t(106–350)\t\nCHE (U/l)\t207\t(218–464)\t\nCRP (mg/dl)\t3.95\t(<0.3)\t\nBlood glucose (mg/dl)\t73\t(72–110)\t\nT. cholesterol (mg/dl)\t95\t(128–220)\t\nTriglyceride (mg/dl)\t60\t(30–150)\t\nHDL cholesterol (mg/dl)\t43\t(40–108)\t\nTSH (μIU/ml)\t0.02\t(0.50–5.00)\t\nfT3 (pg/ml)\t4.60\t(2.30–4.00)\t\nfT4 (ng/dl)\t1.94\t(0.90–1.70)\t\nThyroglobulin (ng/ml)\t195.7\t(<32.7)\t\nTSAb (%)\t104\t(<180)\t\nTg-antibody (IU/ml)\t0.7\t(<28)\t\nTPO-antibody (IU/ml)\t0.3\t(<16)\t\nWBC, white blood cell; RBC, red blood cell; BUN, blood urea nitrogen; TSAb, thyroid stimulating antibody; Tg, thyroglobulin; TPO, thyroid peroxidase.\n\nFigure 1 Ultrasonograph of the thyroid showing diffuse enlargement and posterior attenuation of echogenicity (A and B). The right lobe had a low echoic region that was tender (C, white arrow). On color Doppler imaging, the thyroid gland did not show hypervascularity (D).\n\nFigure 2 Technetium-99m scintigraph of the thyroid.\n\nTreatment\nAs the administration of acetaminophen for another 2 weeks did not ameliorate his symptoms and thyroid dysfunction, oral prednisolone (20 mg/day) was initiated on June 6, 2012. Instantly, his fever and thyroid pain were improved. Treatment with prednisolone was stopped on November 8, 2012 (Fig. 3) because his thyroid function had normalized and his symptoms were gone. His goiter was reduced in size after the treatment with prednisolone, but it remained swollen.\n\nFigure 3 Changes in thyroid function and CRP. Prednisolone (PSL) was administrated from June 2012 to November 2012 and from January 2013 to April 2013 for the treatment of subacute thyroiditis-like symptoms. Treatment with PSL for Crohn's disease was started in September 2013. Levothyroxine Na was prescribed for hypothyroidism in July 2013. Mesalazine and azathioprine were taken for the treatment of Crohn's disease.\n\nHe suffered from diarrhea after the withdrawal of prednisolone; therefore, another TNF inhibitor, adalimumab, was administered starting on December 13, 2012. After three injections, his abdominal symptoms were ameliorated, but his thyroid pain and fever returned on January 10, 2013. The laboratory data on January 16 revealed elevated serum CRP (9.88 mg/dl) without thyroid dysfunction (Fig. 3). Serum Tg had increased from 200.7 ng/ml (December 5, 2012) to 753.2 ng/ml (January 16, 2013). Adalimumab was discontinued, and oral prednisolone (10 mg daily) was restarted. His symptoms vanished immediately after retreatment with prednisolone, but the elastic, firm goiter in the right lobe remained. A fine-needle biopsy of the thyroid gland was performed on November 7, 2013, and it revealed amyloid deposition in his thyroid gland (Fig. 4). Amyloid deposition was histologically confirmed in biopsied tissues from his stomach and duodenum.\n\nFigure 4 Cytological examination of the thyroid tissue obtained using fine-needle biopsy. Abnormal extracellular deposits showed positive staining with Congo red.\n\nOutcome and follow-up\nAs his serum TSH level increased, levothyroxine has been prescribed since July 2013, which has yielded a euthyroid state (Fig. 3).\n\nDiscussion\nThyrotoxicosis in our patient is suspected to have resulted from subacute thyroiditis-like destructive thyroiditis but not from hyperthyroidism, because his fever and thyroid pain disappeared immediately after the treatment with prednisolone. Relatively low uptake on technetium-99m scintigraphy also strongly suggests destructive thyroiditis.\n\nA viral etiology has most often been implicated in subacute thyroiditis. Although serological tests for viruses suspected to be associated with subacute thyroiditis were not performed, our patient reported no episode of viral infection during anti-TNF therapy. Human leukocyte antigen typing showed that he was positive for B44 and B51 but not for B35, which confers an apparent genetic predisposition to subacute thyroiditis (6).\n\nEarly recurrence of subacute thyroiditis (within 12 months after the first episode) is rare, occurring in only 10% of patients with subacute thyroiditis (7). Our patient immediately relapsed with thyroid pain and fever after the treatment with a different anti-TNF agent. Furthermore, although goiters resulting from subacute thyroiditis usually disappear after improvement in thyroid function, in the present case, the patient's thyroid remained swollen following treatment with prednisolone. Therefore, our patient was suspected of having a thyroid disorder different from common subacute thyroiditis. He was then diagnosed with thyroid amyloidosis by fine-needle biopsy.\n\nAmyloidosis is classified as primary and secondary. Secondary amyloidosis mostly accompanies chronic inflammatory diseases, such as tuberculosis, rheumatoid arthritis, and inflammatory bowel disease. One previous study reported that 15 (0.9%) of 1709 patients with Crohn's disease were complicated by secondary amyloidosis and only three patients had amyloid deposition in the thyroid (8).\n\nThyroid function in patients with an amyloid goiter is usually normal. However, several cases have been reported involving hyperthyroxinemia with an amyloid goiter that might have resulted from destructive thyroiditis, as was the case with our patient (9)\n(10). Although subacute thyroiditis more frequently affects women than men (7), thyroid amyloidosis with subacute thyroiditis-like symptoms has been reported mainly in men.\n\nIt is difficult to verify that the patient had thyroid amyloidosis before the administration of the first anti-TNF inhibitor, infliximab, because he did not undergo any examinations of the thyroid, including ultrasonography or needle biopsy, before the administration of the inhibitor. Serum thyroglobulin was elevated after the administration of the second anti-TNF inhibitor, adalimumab. This strongly suggests that anti-TNF inhibitors triggered the destructive thyroiditis-like subacute thyroiditis in the patient. How TNF inhibitors could trigger subacute thyroiditis-like symptoms in our patient is unknown. Infliximab and adalimumab are monoclonal antibodies directed against TNF-α, and both have been established as a new standard for the treatment of Crohn's disease. A patient who developed Graves’ disease during treatment with adalimumab has been reported (11), but no case involving destructive thyroiditis during treatment with both inhibitors was found in the literature. Etanercept is a TNF inhibitor that acts as a decoy receptor for TNF-α by competitively inhibiting the binding of TNF-α to its cell surface receptor. Several reports describe patients developing thyrotoxicosis while on etanercept (2)\n(3)\n(4)\n(5). All of these patients were initially suspected of having subacute thyroiditis because they showed thyroid pain without thyroid antibodies, but no thyroid amyloidosis was documented. All of these patients happened to develop subacute thyroiditis at least 6 months after the initiation of etanercept treatment. However, the subacute thyroiditis-like symptoms in our patient occurred immediately after the initiation of infliximab and adalimumab.\n\nTNF-α and TNF-α receptors reside in human thyroid tissue (12). Anti-TNF-α antibody suppresses thyroidal fibrosis in mouse with granulomatous experimental autoimmune thyroiditis (13). Therefore, TNF signaling likely regulates the structure and function of the thyroid. Thus, modulation of the immune system by TNF inhibitors that are similar to interferon may induce thyroid dysfunction.\n\nWe described a case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF therapy. The precise mechanism underlying the onset of this condition remains unclear. Further studies are of interest to elucidate the pathogenesis of subacute thyroiditis.\n\nPatient consent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nAuthor contribution statement\nJ Kawashima was the lead clinician who managed the patient's thyroid disorder; H Naoe was the lead clinician who managed the patient's Crohn's disease; all authors contributed to the drafting of the report.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n==== Refs\nReferences\n1 \n\nSurks \nMI \n & \nSievert \nR \n. 1995 \nDrugs and thyroid function . New England Journal of Medicine \n333 \n1688 –1694 . 10.1056/NEJM199512213332507 \n7477223 \n2 \n\nAllanore \nY \n, \nBremont \nC \n, \nKahan \nA \n & \nMenkes \nCJ \n. 2001 \nTransient hyperthyroidism in a patient with rheumatoid arthritis treated by etanercept . Clinical and Experimental Rheumatology \n19 \n356 –357 .11407100 \n3 \n\nVassilopoulos \nD \n, \nSialevris \nK \n, \nMalahtari \nS \n, \nDeutsch \nM \n, \nManolakopoulos \nS \n & \nArchimandritis \nAJ \n. 2010 \nSubacute thyroiditis presenting as fever of unknown origin in a patient with rheumatoid arthritis under etanercept treatment . Journal of Clinical Rheumatology \n16 \n88 –89 . 10.1097/RHU.0b013e3181d0bd30 \n20216130 \n4 \n\nCanas \nCA \n, \nTobon \nGJ \n, \nArango \nLG \n & \nGuarin \nN \n. 2009 \nDeveloping of granulomatous thyroiditis during etanercept therapy . Clinical Rheumatology \n28 \nS17 –S19 . 10.1007/s10067-008-1046-2 \n19043773 \n5 \n\nYasuji \nI \n. 2013 \nSubacute thyroiditis in a patient with juvenile idiopathic arthritis undergoing etanercept treatment: a case report and review of the literature . Modern Rheumatology \n23 \n397 –400 . 10.3109/s10165-012-0670-5 \n22669598 \n6 \n\nOhsako \nN \n, \nTamai \nH \n, \nSudo \nT \n, \nMukuta \nT \n, \nTanaka \nH \n, \nKuma \nK \n, \nKimura \nA \n & \nSasazuki \nT \n. 1995 \nClinical characteristics of subacute thyroiditis classified according to human leukocyte antigen typing . Journal of Clinical Endocrinology and Metabolism \n80 \n3653 –3656 . 10.1210/jcem.80.12.8530615 \n8530615 \n7 \n\nFatourechi \nV \n, \nAniszewski \nJP \n, \nFatourechi \nGZ \n, \nAtkinson \nEJ \n & \nJacobsen \nSJ \n. 2003 \nClinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study . Journal of Clinical Endocrinology and Metabolism \n88 \n2100 –2105 . 10.1210/jc.2002-021799 \n12727961 \n8 \n\nGreenstein \nAJ \n, \nSachar \nDB \n, \nPanday \nAK \n, \nDikman \nSH \n, \nMeyers \nS \n, \nHeimann \nT \n, \nGumaste \nV \n, \nWerther \nJL \n & \nJanowitz \nHD \n. 1992 \nAmyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients . Medicine \n71 \n261 –270 . 10.1097/00005792-199209000-00001 \n1522802 \n9 \n\nIkenoue \nH \n, \nOkamura \nK \n, \nKuroda \nT \n, \nSato \nK \n, \nYoshinari \nM \n & \nFujishima \nM \n. 1988 \nThyroid amyloidosis with recurrent subacute thyroiditis-like syndrome . Journal of Clinical Endocrinology and Metabolism \n67 \n41 –45 . 10.1210/jcem-67-1-41 \n3379135 \n10 \n\nNagai \nY \n, \nOhta \nM \n, \nYokoyama \nH \n, \nTakamura \nT \n & \nKobayashi \nKI \n. 1998 \nAmyloid goiter presented as a subacute thyroiditis-like symptom in a patient with hypersensitivity vasculitis . Endocrine Journal \n45 \n421 –425 . 10.1507/endocrj.45.421 \n9790279 \n11 \n\nvan Lieshout \nAW \n, \nCreemers \nMC \n, \nRadstake \nTR \n, \nElving \nLD \n & \nvan Riel \nPL \n. 2008 \nGraves' disease in a patient with rheumatoid arthritis during treatment with anti-tumor necrosis factor-α . Journal of Rheumatology \n35 \n938 –939 .18464319 \n12 \n\nZubelewicz \nB \n, \nMuc-Wierzgon \nM \n, \nWierzgon \nJ \n, \nRomanowski \nW \n, \nMazurek \nU \n, \nWilczok \nT \n & \nPodwinska \nE \n. 2002 \nGenetic disregulation of gene coding tumor necrosis factor α receptors (TNF α Rs) in follicular thyroid cancer – preliminary report . Journal of Biological Regulators and Homeostatic Agents \n16 \n98 –104 .12144133 \n13 \n\nChen \nK \n, \nWei \nY \n, \nSharp \nGC \n & \nBraley-Mullen \nH \n. 2007 \nDecreasing TNF-α results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis . Journal of Leukocyte Biology \n81 \n306 –314 . 10.1189/jlb.0606402 \n17046971\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-0573", "issue": "2015()", "journal": "Endocrinology, diabetes & metabolism case reports", "keywords": null, "medline_ta": "Endocrinol Diabetes Metab Case Rep", "mesh_terms": null, "nlm_unique_id": "101618943", "other_id": null, "pages": "140117", "pmc": null, "pmid": "25969738", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "19043773;12144133;11407100;17046971;20216130;3379135;7477223;12727961;18464319;9790279;8530615;22669598;1522802", "title": "A rare case showing subacute thyroiditis-like symptoms with amyloid goiter after anti-tumor necrosis factor therapy.", "title_normalized": "a rare case showing subacute thyroiditis like symptoms with amyloid goiter after anti tumor necrosis factor therapy" }	[ { "companynumb": "JP-JNJFOC-20131016692", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": "20120509", "drugenddateformat": "102", "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20120509", "drugstartdateformat": "102", "drugstructuredosagenumb": "252", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOSTRIDIUM BUTYRICUM SPORES STRAIN M-55" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIYA-BM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTASA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": "20120426", "drugenddateformat": "102", "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20120426", "drugstartdateformat": "102", "drugstructuredosagenumb": "252", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Goitre", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Thyroiditis subacute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2012" } }, "primarysource": { "literaturereference": "KAWASHIMA J, NAOE H, SASAKI Y, ARAKI E. A RARE CASE SHOWING SUBACUTE THYROIDITIS-LIKE SYMPTOMS WITH AMYLOID GOITER AFTER ANTI-TUMOR NECROSIS FACTOR THERAPY.. ENDOCRINOLOGY, DIABETES AND METABOLISM CASE REPORTS MAY-2015:14-0117. KAWASHIMA J, KUKIDOME D, IGATA M, KONDO T, TSURUZOE K, SHIMODA S, ET AL. A CASE OF SUBACUTE THYROIDITIS THAT DEVELOPED AFTER STARTING ANTI-TNF ALPHA ANTIBODY THERAPY TO TREAT CROHN^S DISEASE. THE JAPANESE JOURNAL OF ENDOCRINOLOGY 2013;89 (2):502.", "literaturereference_normalized": "a rare case showing subacute thyroiditis like symptoms with amyloid goiter after anti tumor necrosis factor therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150528", "receivedate": "20131031", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9659674, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "Nontraditional combination of existing therapies is often the only option to avoid surgery in refractory inflammatory bowel disease (IBD) patients. We aim to assess the efficacy and safety of concomitant use of 2 biologic therapies or combination of biologic and tofacitinib in a refractory pediatric IBD cohort.\n\n\n\nAs part of an ongoing single-center observational cohort study of therapeutic outcomes in pediatric IBD patients (younger than 18 years), data were collected for patients receiving dual therapy. Primary outcome was 6 months of steroid-free remission. Secondary outcomes included time to steroid-free remission, change in serum biomarkers (C-reactive protein and erythrocyte sedimentation rate) and albumin between baseline and 6 months, and adverse events.\n\n\n\nSixteen children (9 ulcerative colitis/IBD-unspecified, 7 Crohn's disease), with a disease duration of 3 (2.1-5.0) years, initiated dual therapy at an age of 15.9 (13.5-16.8) years after failing ≥2 biologic therapies. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn's disease ) achieved steroid-free remission at 6 months. Erythrocyte sedimentation rate and C-reactive protein decreased (P = 0.021 and P = 0.015, respectively) and albumin increased (P = 0.003) between baseline and 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis.\n\n\n\nOur data suggest that dual therapy may be an option for patients with limited therapeutic options remaining. Safety concerns should always be at the forefront of decision-making, and larger studies are needed to help confirm the preliminary safety data observed.", "affiliations": "Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.", "authors": "Dolinger\|Michael T\|MT\|;Spencer\|Elizabeth A\|EA\|0000-0002-6787-1164;Lai\|Joanne\|J\|;Dunkin\|David\|D\|;Dubinsky\|Marla C\|MC\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ibd/izaa277", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0998", "issue": "27(8)", "journal": "Inflammatory bowel diseases", "keywords": "Crohn’s disease; biologics; inflammatory bowel disease; pediatric gastroenterology; ulcerative colitis", "medline_ta": "Inflamm Bowel Dis", "mesh_terms": null, "nlm_unique_id": "9508162", "other_id": null, "pages": "1210-1214", "pmc": null, "pmid": "33125058", "pubdate": "2021-07-27", "publication_types": "D016428:Journal Article", "references": null, "title": "Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease.", "title_normalized": "dual biologic and small molecule therapy for the treatment of refractory pediatric inflammatory bowel disease" }	[ { "companynumb": "US-PFIZER INC-2020444740", 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{ "abstract": "A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML.", "affiliations": "Department of Neurology, Kobe City Medical Center General Hospital, Japan.;Department of Anatomic Pathology, Tokyo Medical University, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, Japan.;Department of Pathology, Kobe City Medical Center General Hospital, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, Japan.", "authors": "Ishii\|Junko\|J\|;Shishido-Hara\|Yukiko\|Y\|;Kawamoto\|Michi\|M\|;Fujiwara\|Satoru\|S\|;Imai\|Yukihiro\|Y\|;Nakamichi\|Kazuo\|K\|;Kohara\|Nobuo\|N\|", "chemical_list": "D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D015767:Mefloquine", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.0696-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2970994710.2169/internalmedicine.0696-17Case ReportA Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study Ishii Junko 1Shishido-Hara Yukiko 2Kawamoto Michi 1Fujiwara Satoru 1Imai Yukihiro 3Nakamichi Kazuo 4Kohara Nobuo 1\n1 Department of Neurology, Kobe City Medical Center General Hospital, Japan\n2 Department of Anatomic Pathology, Tokyo Medical University, Japan\n3 Department of Pathology, Kobe City Medical Center General Hospital, Japan\n4 Department of Virology 1, National Institute of Infectious Diseases, JapanCorrespondence to Dr.　Junko Ishii, [email protected]\n\n27 4 2018 15 9 2018 57 18 2727 2734 20 12 2017 7 2 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML. \n\nprogressive multifocal leukoencephalopathy (PML)systemic lupus erythematosus (SLE)punctate pattern, pathological examinationearly diagnosismefloquine\n==== Body\nIntroduction\nProgressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by the reactivation of latent JC virus (JCV) infection. Although the life cycle and molecular pathogenesis of JCV have not been completely elucidated yet, nonpathogenic “archetype” JCV may occasionally transform into the “neurotropic type (PML-type)”, which is thought to cause PML according to the “archetype hypothesis” (1-3).\n\nThis disease was previously known as a complication of AIDS, but at present, PML development due to the use of immunomodulatory drugs, such as natalizumab (NTZ) for multiple sclerosis (MS), is a serious concern (4). PML can be comorbid with autoimmune disorders, such as systemic lupus erythematosus (SLE), when the patient is under immunosuppressant therapy (5). Brain magnetic resonance imaging (MRI) in cases of PML typically shows large subcortical lesions with an increased T2-weighted signal and correlates with rapid progression that usually leads to a poor prognosis (6). Recently, in NTZ-treated MS patients, atypical MRI findings with a punctate pattern have been reported as an early sign of PML (7, 8-10), but whether or not these images are also indicative of early PML lesions in non-MS patients is unclear.\n\nWe herein report a case of pathologically-proven PML in a patient with SLE, who showed a punctate MRI pattern and a good clinical course. The pathology suggested a relatively low viral replication in the infected cells that may be indicative of the early demyelinating stage, supporting a better prognosis.\n\nCase Report\nA 37-year-old woman had been diagnosed with SLE at 12 years of age. SLE recurred several times despite combination therapy with high-dose intravenous methylprednisolone, oral prednisolone (PSL), azathioprine (AZA), and 6-mercaptopurine. At 16 and 17 years of age, plasmapheresis and high-dose intravenous cyclophosphamide therapy (IVCY) were introduced, respectively, to control the disease. At 17 years of age, she experienced insomnia, auditory hallucinations, and convulsive seizures, indicating neuropsychiatric SLE (NPSLE). Thus, an antiepileptic drug was temporarily administered. At 18 years of age, she had severe lupus nephritis with nephrotic syndrome. As the lupus nephritis was refractory, the treatment was changed from PSL+AZA+IVCY to PSL+cyclosporine+IVCY at 20 years of age. At 23 years of age, she underwent hemodialysis for about 8 months, and LDL apheresis was introduced. As she experienced convulsive seizures again, NPSLE was suspected and an antiepileptic drug was temporarily administered. At 27 years of age, immunoadsorption plasmapheresis was performed. From 28 years of age, her SLE symptoms were suppressed with PSL+cyclosporine. At 32 years of age, cyclosporine was switched to mycophenolate mofetil (MMF) for better control of the disease. Since then, SLE and lupus nephritis had been relatively well controlled with PSL 8-10 mg/day+MMF 1,000-1,250 mg/day despite a long history of refractory SLE.\n\nApproximately five months before the initial visit to our department, she began experiencing gait disturbance and cognitive dysfunction, and these symptoms slowly became exacerbated. At the initial visit, brain MRI revealed small, punctate, T2-/fluid-attenuated inversion recovery (FLAIR)-hyperintense and T1-hypointense lesions without gadolinium (Gd) enhancement in the bilateral cerebral peduncles, internal capsule, corpus callosum, and deep white matter of the left frontal lobe and bilateral periventricular area (Fig. 1). SLE-related vasculitis was suspected, as she had a long history of refractory SLE and lupus nephritis with NPSLE, and the size and distribution of MRI lesions resembled those reported in patients with NPSLE (11, 12). However, blood tests showed no exacerbation of SLE, and Gd enhancement was not apparent on brain MRI. We also considered PML as a differential diagnosis; however, PML was thought to be unlikely due to the lack of U-fiber involvement and the atypical MR images.\n\nFigure 1. Brain MRI findings at the initial visit (A: FLAIR images, B: T1-weighted images, C: diffusion-weighted images, D: T1-weighted images with gadolinium enhancement). FLAIR images (A) show high-intensity areas in the bilateral cerebral peduncles, internal capsule, corpus callosum, and deep white matter of the left frontal lobe and bilateral periventricular area. These lesions show a small punctate pattern without U-fiber involvement (A: enlarged view). These punctate lesions are scattered in the vicinity of the larger merged lesion in the left frontal lobe. Small punctate lesions are clearly visualized as low-intensity signals on T1-weighted images (B: axial and sagittal) in the deep white matter and internal capsule. The lesions appear as slightly high-intensity signals on diffusion-weighted images (C) and do not show any enhancement after gadolinium administration on T1-weighted images (D). The arrows in the FLAIR image, T1-weighted image, and diffusion-weighted images show the biopsied area (A, B, and C). FLAIR: fluid-attenuated inversion recovery, DWI: diffusion-weighted images, Gd: gadolinium\n\nPolymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) revealed the presence of JCV DNA (at most 500 copies/mL), but repeated trials were sometimes JCV-negative. The serum was positive for anti-JCV antibody (Index 2.24), which is associated with an increased risk of PML in patients with a history of NTZ treatment (4, 13), although this patient had not been treated with NTZ. The CD4+ T cell count was 148 cells/μL. T-CD4+ lymphopenia is reported to be associated with a risk of PML in patients with SLE (14). We reduced the dose of PSL from 8 to 7 mg and carefully observed the clinical symptoms, MRI findings, and JCV DNA in the CSF. Brain MRI may have shown a slight improvement, and gait disturbance and cognitive disorder were slightly exacerbated over the next four months. Although we detected JCV DNA in the CSF, it did not increase for more than four months.\n\nThe inconsistent detection of JCV DNA in the CSF, atypical brain MRI findings, and the clinical course prevented us from confirming the diagnosis in the present patient. As the treatment for PML is quite different from that for SLE-related vasculitis, it is important to verify the diagnosis. Because SLE-related vasculitis could not be ruled out, a brain biopsy of the corpus callosum (Fig. 1, arrow) was performed. We also examined the nucleotide sequences of the JCV genome in the CSF and brain tissues to clarify whether or not the JCV was PML-type.\n\nPathological detection of JCV-infected glial cells\nSix pieces of fragmented brain tissues, up to approximately 1×5 mm in size, were obtained. In hematoxylin/eosin staining, numerous macrophages were apparent (Fig. 2A), compatible with a demyelinating lesion. Although astroglia with large bizarre nuclei were present (Fig. 2B), oligodendroglia-like cells with typical JCV inclusions were hardly detected. Immunohistochemical labeling of two pieces of brain tissues showed decreased GFAP signals with an elevated number of CD68-positive cells (Fig. 2C and D) in contrast to four other pieces with normal GFAP signals and relatively few CD68-positive cells (Fig. 2E and F). The former two pieces were more severely damaged than the latter four, and atypical astrocytes with bizarre nuclei were present.\n\nFigure 2. Pathology of early PML. A, B: Biopsied brain tissues show atypical astroglia with large irregular nuclei (arrow), but oligodendroglia-like cells with typical JCV inclusions were hardly detectable with Hematoxylin and Eosin staining. C, D: One piece of brain tissue showed decreased GFAP signals with an elevated CD68-positive cell density, suggesting advanced tissue degradation. C: GFAP, D: CD68. E, F: Another piece was rather mildly affected with relatively normal GFAP signals and a lower CD68-positive cell density. E: GFAP, F: CD68. G: Immunohistochemistry (IHC) for JCV capsid proteins. JCV-positive cells were hardly detected with immunohistochemistry, except for one potentially positive cell (inset). H: In situ hybridization (ISH) for JCV DNA. ISH detected more than 20 JCV-positive cells (circled in red), with the largest number of positive cells observed in tissues with higher CD68-positive cell density. I-L: JCV-positive cells with ISH. All cells contained punctate signals in the enlarged nuclei, compatible with clustered JCV virions, represented as dot-shaped inclusions. Scale bars: (A) 200 µm; (B) 50 µm; (C-F) 1 mm; (G, H) 500 µm; (I-L) 25 µm. PML: progressive multifocal leukoencephalopathy, JCV: JC virus\n\nImmunohistochemistry with anti-JCV antibodies (VP1, VP2/VP3C) was performed, and only one potentially JCV-positive cell was detected with the anti-JCV VP1 antibody (Fig. 2G, inset); infected cells were not clearly positive with the anti-JCV VP2/VP3C antibody (data not shown). However, a more sensitive in situ hybridization (ISH) method targeting JCV DNA revealed more than 20 JCV-positive oligodendroglia-like cells. Most JCV-positive cells were present in the two pieces of brain tissue with the higher CD68-positive cell density (Fig. 2H). All JCV-positive cells showed intranuclear punctate signals indicative of clustered JCV progenies at promyelocytic leukemia nuclear bodies (Fig. 2I-L). The host inflammatory response was minimal, and only a few CD3-positive T cells were observed. Nearly equal numbers of CD4- and CD8-positive cells were present. Inflammatory cells of the B-cell lineage were also examined, but immunoreactivity for CD20, CD79a, and CD138 was not detectable (data not shown). These findings argued against SLE-related vasculitis.\n\nThe JCV genome in the CSF and brain tissues was cloned, and the nucleotide sequences were examined. Apparent mutations (deletion and insertions) characteristic of the PML-type virus were found in the non-coding control region (NCCR) (Fig. 3). Based on these pathological findings and the nucleotide sequence analysis, the diagnosis of PML was confirmed.\n\nFigure 3. A comparison of the JCV non-coding control region (NCCR) sequence pattern. The NCCR sequence patterns in the CSF and brain tissues from this patient were compared with the archetype (CY) and PML-type NCCRs (Mad-1). The horizontal gray lines indicate the DNA fragments identical to the archetype NCCR (5' and 3' nucleotide positions 1-267 within the JCV genotype). The black lines indicate the duplicated sequences inserted into the deleted region. The nucleotide numbers corresponding to the archetype NCCR are shown above or below the solid lines. CSF: cerebrospinal fluid, PML: progressive multifocal leukoencephalopathy\n\nClinical course after the brain biopsy\nOnce the diagnosis was confirmed, MMF was gradually tapered off, and mefloquine was administered (loading dose of 275 mg for 3 days, followed by 275 mg once per week). Brain MRI revealed a gradual improvement in the lesions, and no new lesions developed after these therapeutic interventions. The PCR analysis of the CSF was negative for JCV DNA, 7 months after the brain biopsy, and it has been consistently negative for the past 12 months. The number of CD4+ T cells changed slightly, but no definite trend has been observed so far. Cognitive dysfunction improved slightly without ataxic deterioration (Fig. 4). The patient has been stable for over 18 months.\n\nFigure 4. A summary of the clinical course of the diagnostic and therapeutic procedures with corresponding MR images. The timeline shown above represents the clinical course (24 months) after the first visit. Of note, punctate lesions in the deep white matter and internal capsule on FLAIR images gradually disappeared, and no new lesions have developed since the tapering-off of mycophenolate mofetil and the administration of mefloquine. The CSF was negative for JCV DNA at 11 months and has remained negative for the past 12 months. The ataxia has not worsened, and cognitive dysfunction has improved slightly. The patient has been stable for more than 18 months since the brain biopsy. JCV: JC virus, CSF: cerebrospinal fluid, MMSE: Mini Mental State Examination, FLAIR: fluid- attenuated inversion recovery\n\nDiscussion\nRecently, PML development resulting from the use of immunomodulatory drugs has become a serious concern, and JCV in particular is known to reactivate with disease-modifying MS therapies, such as NTZ. The early diagnosis of PML is crucial, and rare MR images of a punctate pattern in the deep white matter have been described as a promising early sign for the diagnosis of NTZ-associated PML (7-10). Contrast enhancement with the punctate pattern may suggest PML-immune reconstitution inflammatory syndrome or productive JCV infection (8, 15). However, whether or not this unique MR pattern is also indicative of PML in non-MS patients has been unclear, and the relevance of this pattern to the underlying histopathology also remains to be elucidated. This is the first case in which a punctate pattern was observed on MRI in a patient with SLE, and an early stage of PML was pathologically proven.\n\nMRI in the present case revealed small, punctate, T2-/FLAIR-hyperintense and T1-hypointense lesions in the bilateral cerebral peduncles, internal capsule, corpus callosum, and deep white matter of the left frontal lobe and bilateral periventricular area. Because these images were completely different from those observed in previously reported PML cases with SLE (5, 16, 17), it was difficult to diagnose this case with PML based on the MRI findings alone, and it was possible to suspect SLE-related vasculitis (11, 12). Although PCR showed that the CSF was positive for JCV DNA (500 copies/mL) at the initial visit, the brain MRI findings and the clinical course were atypical for PML. The commonly used PCR method for detecting JCV DNA targets the large T antigen of JCV and cannot distinguish PML-type JCV from archetype JCV. The CSF of our patient may have contained archetype JCV. Thus, the detection of JCV DNA in the CSF by PCR was not sufficient to establish a definite diagnosis in an atypical case such as this.\n\nIn our patient, punctate MRI lesions were scattered in the vicinity of the larger merged lesion in the left frontal lobe, resembling the “milky way appearance” reportedly observed at the early stages in patients with NTZ-associated PML (8, 18). We therefore considered that this MRI pattern might similarly indicate an early stage of PML in our patient with SLE. However, the atypical clinical course and MRI findings alone were insufficient to confirm the diagnosis. We therefore performed a brain biopsy, resulting in a definite diagnosis of PML. Of note, this unique punctate MRI pattern was observed in a case of non-NTZ-associated PML. Some PML cases in patients with psoriasis were reported to display punctate lesions on MRI, although the MRI findings were not well-described (19, 20). The punctate pattern may not be specific for NTZ-associated PML but instead ubiquitous for PML.\n\nWe first analyzed the pathology of early-stage PML showing a punctate MRI pattern. Despite the presence of relatively large T2-/FLAIR-hyperintense lesions, JCV-infected oligodendroglia-like cells were hardly detected with histological staining and immunolabeling; however, more than 20 JCV-positive cells were detected with sensitive ISH. These data indicate that regardless of the number of JCV-infected cells, the viral replication rate in each cell was relatively low, resulting in only mild tissue degeneration. JCV DNA in the CSF was not always detected in repeated PCR trials, which may indicate low viral replication, consistent with the pathological findings. Biopsied brain tissue specimens are usually tiny, and the JCV-infected oligodendroglia-like cells were scattered in the samples we obtained. Our samples may therefore not have contained any affected lesions simply due to technical limitations. In our patient, one of the biopsied brain tissues fortunately contained a sufficient number of JCV-positive cells to confirm the diagnosis. We cannot deny the possibility that biopsied samples from other areas with strongly hypointense signals on T1-weighted images might have revealed more severe pathological changes with abundant populations of JCV-positive cells. Although early cytopathological changes, including the dot-shaped inclusions in JCV-infected cells, have been studied (3, 21), most of our knowledge about PML pathology is derived from autopsied cases typically associated with HIV infection (22). Thus, the present case is important for its novelty. Furthering our understanding of early PML pathology will aid in the diagnosis of biopsied brain tissues.\n\nWhen the immunosuppressant was tapered off and mefloquine was administered, the T2-/FLAIR-hyperintense lesions gradually diminished in size, and the patient has remained stable over the long term. A punctate MRI pattern is not specific to NTZ-associated PML, and an awareness of this unique MRI pattern will aid in the early diagnosis of PML, leading to the early treatment and a better prognosis.\n\n\nThe treatment with mefloquine was approved by our hospital Ethics Committee. We obtained written informed consent from the patient.\n\nFinancial Support\nThis work was supported in part by JSPS KAKENHI (Grand Number 17K09768 and 15K06759) and by a Grant-in-Aid for the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant Number H29-Nanchitou (Nan)-Ippan-036).\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank Takayuki Funatsu for performing the brain biopsy, Souichi Nukuzuma and Masayuki Saijo for the analysis of JCV in the CSF, and Kenta Takahashi for the analysis of JCV in the biopsied brain tissues.\n==== Refs\n1. \nTan CS , Koralnik IJ \nProgressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis . Lancet Neurol \n9 : 425 -437 , 2010 .20298966 \n2. \nWhite MK , Khalili K \nPathogenesis of progressive multifocal leukoencephalopathy--revisited . J Infect Dis \n203 : 578 -586 , 2011 .21227915 \n3. \nShishido-Hara Y \nProgressive multifocal leukoencephalopathy and promyelocytic leukemia nuclear bodies: a review of clinical, neuropathological, and virological aspects of JC virus-induced demyelinating disease . Acta Neuropathol \n120 : 403 -417 , 2010 .20464404 \n4. \nSchwab N , Schneider-Hohendorf T , Melzer N , Cutter G , Wiendl H \nNatalizumab-associated PML: challenges with incidence, resulting risk, and risk stratification . Neurology \n88 : 1197 -1205 , 2017 .28228564 \n5. \nHenegar CE , Eudy AM , Kharat V , Hill DD , Bennett D , Haight B \nProgressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review . Lupus \n25 : 617 -626 , 2016 .26743322 \n6. \nSahraian MA , Radue EW , Eshaghi A , Besliu S , Minagar A \nProgressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis . Eur J Neurol \n19 : 1060 -1069 , 2012 .22136455 \n7. \nPhan-Ba R , Lommers E , Tshibanda L , et al \nMRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy . J Neurol Neurosurg Psychiatry \n83 : 224 -226 , 2012 .22013244 \n8. \nHodel J , Darchis C , Outteryck O , et al \nPunctate pattern: a promising imaging marker for the diagnosis of natalizumab-associated PML . Neurology \n86 : 1516 -1523 , 2016 .27009257 \n9. \nWijburg MT , Witte BI , Vennegoor A , et al \nMRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance . J Neurol Neurosurg Psychiatry \n87 : 1138 -1145 , 2016 .27530808 \n10. \nHodel J , Outteryck O , Dubron C , et al \nAsymptomatic progressive multifocal leukoencephalopathy associated with natalizumab: diagnostic precision with MR imaging . Radiology \n278 : 863 -872 , 2016 .26436861 \n11. \nBertsias GK , Boumpas DT \nPathogenesis, diagnosis and management of neuropsychiatric SLE manifestations . Nat Rev Rheumatol \n6 : 358 -367 , 2010 .20458332 \n12. \nJennings JE , Sundgren PC , Attwood J , McCune J , Maly P \nValue of MRI of the brain in patients with systemic lupus erythematosus and neurologic disturbance . Neuroradiology \n46 : 15 -21 , 2004 .14648006 \n13. \nPlavina T , Subramanyam M , Bloomgren G , et al \nAnti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy . Ann Neurol \n76 : 802 -812 , 2014 .25273271 \n14. \nBrandao M , Damasio J , Marinho A , et al \nSystemic lupus erythematosus, progressive multifocal leukoencephalopathy, and T-CD4+ lymphopenia . Clin Rev Allergy Immunol \n43 : 302 -307 , 2012 .22674017 \n15. \nWattjes MP , Verhoeff L , Zentjens W , et al \nPunctate lesion pattern suggestive of perivascular inflammation in acute natalizumab-associated progressive multifocal leukoencephalopathy: productive JC virus infection or preclinical PML-IRIS manifestation? \nJ Neurol Neurosurg Psychiatry \n84 : 1176 -1177 , 2013 .23695498 \n16. \nFredericks CA , Kvam KA , Bear J , Crabtree GS , Josephson SA \nA case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab . Lupus \n23 : 711 -713 , 2014 .24531080 \n17. \nBeppu M , Kawamoto M , Nukuzuma S , Kohara N \nMefloquine improved progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus . Intern Med \n51 : 1245 -1247 , 2012 .22687798 \n18. \nSinnecker T , Othman J , Kuhl M , et al \n7T MRI in natalizumab-associated PML and ongoing MS disease activity: a case study . Neurol Neuroimmunol Neuroinflamm \n2 : e171 , 2015 .26568970 \n19. \nGieselbach RJ , Muller-Hansma AH , Wijburg MT , et al \nProgressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases . J Neurol \n264 : 1155 -1164 , 2017 .28536921 \n20. \nBartsch T , Rempe T , Wrede A , et al \nProgressive neurologic dysfunction in a psoriasis patient treated with dimethyl fumarate . Ann Neurol \n78 : 501 -514 , 2015 .26150206 \n21. \nShishido-Hara Y , Yazawa T , Nagane M , et al \nJC virus inclusions in progressive multifocal leukoencephalopathy: scaffolding promyelocytic leukemia nuclear bodies grow with cell cycle transition through an S-to-G2-like state in enlarging oligodendrocyte nuclei . J Neuropathol Exp Neurol \n73 : 442 -453 , 2014 .24709678 \n22. \nBerger JR , Aksamit AJ , Clifford DB , et al \nPML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section . Neurology \n80 : 1430 -1438 , 2013 .23568998\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(18)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "early diagnosis; mefloquine; progressive multifocal leukoencephalopathy (PML); punctate pattern, pathological examination; systemic lupus erythematosus (SLE)", "medline_ta": "Intern Med", "mesh_terms": "D000328:Adult; D001706:Biopsy; D001921:Brain; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D017403:In Situ Hybridization; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008180:Lupus Erythematosus, Systemic; D008279:Magnetic Resonance Imaging; D015767:Mefloquine; D000069442:Natalizumab", "nlm_unique_id": "9204241", "other_id": null, "pages": "2727-2734", "pmc": null, "pmid": "29709947", "pubdate": "2018-09-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20464404;28536921;21227915;28228564;23568998;24531080;27530808;20298966;27009257;26743322;25273271;23695498;14648006;24709678;22687798;22674017;26150206;26436861;26568970;22136455;22013244;20458332", "title": "A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study.", "title_normalized": "a punctate magnetic resonance imaging pattern in a patient with systemic lupus erythematosus is an early sign of progressive multifocal leukoencephalopathy a clinicopathological study" }	[ { "companynumb": "JP-TEVA-2018-JP-972126", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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A PUNCTATE MAGNETIC RESONANCE IMAGING PATTERN IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS IS AN EARLY SIGN OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY: A CLINICOPATHOLOGICAL STUDY. INTERN-MED 2018?57(18):2727-2734.", "literaturereference_normalized": "a punctate magnetic resonance imaging pattern in a patient with systemic lupus erythematosus is an early sign of progressive multifocal leukoencephalopathy a clinicopathological study", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181102", "receivedate": "20181102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15577705, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control.", "affiliations": "Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.", "authors": "Furukawa\|Sachiko\|S\|;Oobu\|Kazunari\|K\|;Moriyama\|Masafumi\|M\|;Kawano\|Shintaro\|S\|;Sako\|Saori\|S\|;Hayashida\|Jun-Nosuke\|JN\|;Matsubara\|Ryota\|R\|;Ogata\|Ken-Ichi\|KI\|;Kiyoshima\|Tamotsu\|T\|;Nakamura\|Seiji\|S\|", "chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8946-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2922524510.2169/internalmedicine.8946-17Case ReportOral Methotrexate-related Lymphoproliferative Disease Presenting with Severe Osteonecrosis of the Jaw: A Case Report and Literature Review Furukawa Sachiko 1Oobu Kazunari 1Moriyama Masafumi 12Kawano Shintaro 1Sako Saori 1Hayashida Jun-Nosuke 1Matsubara Ryota 1Ogata Ken-Ichi 1Kiyoshima Tamotsu 3Nakamura Seiji 1\n1 Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan\n2 OBT Research Center, Faculty of Dental Science, Kyushu University, Japan\n3 Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, JapanCorrespondence to Dr.　Kazunari Oobu, [email protected]\n\n8 12 2017 15 2 2018 57 4 575 581 30 1 2017 17 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control. \n\nmethotrexate-related lymphoproliferative disordermedication-related osteonecrosis of the jawrheumatoid arthritislymphomaEpstein-Barr virus\n==== Body\nIntroduction\nMethotrexate (MTX) is the current first-line treatment for rheumatoid arthritis (RA) (1). However, many recent case studies have reported that long-term MTX treatment resulted in MTX-related lymphoproliferative disorder (MTX-LPD) in RA patients (2,3). The recent World Health Organization classification of lymphoid neoplasms categorizes MTX-LPD as an “other iatrogenic immunodeficiency-associated LPD” (4). MTX-LPD may resolve several weeks after the withdrawal of MTX therapy; however, additional treatments, such as chemotherapy and radiotherapy, should be considered for patients with persistent LPD after MTX withdrawal (5-7). Regarding the mechanism underlying the onset of MTX-LPD, it is considered that immunosuppression by MTX reduces the host immunosurveillance of Epstein-Barr virus (EBV)-infected B cells, because approximately 50% of patients with MTX-LPD are EBV-positive (8).\n\nBisphosphonates (BPs) are the primary treatment for osteoporosis, bone metastasis, hypercalcemia caused by malignancies, Paget disease of bone, and osteolytic lesions of multiple myeloma. Although BP treatment has many benefits for patients with skeletal complications, it is associated with a number of adverse effects, the most important of which is BP-related osteonecrosis of the jaw (BRONJ) (9,10). Since BRONJ was first reported in 2003, many additional cases have been reported (11,12). Because osteonecrosis of the jaw can also be caused by other drugs, the American Association of Oral and Maxillofacial Surgery updated their position paper on BRONJ in 2014. The term BRONJ was replaced with medication-related osteonecrosis of the jaw (MRONJ) (13). The clinical manifestations of MRONJ include soft tissue swelling, fistula, abscess, pain, and bone exposure (14). There is currently no gold standard for the treatment of MRONJ or MTX-LPD. MTX-LPD generally develops at extra-nodal sites (8). To the best of our knowledge MTX-LPD of the oral cavity is rare, and no previous studies have reported the serial treatment of MTX-LPD with MRONJ.\n\nWe herein describe a case of MTX-LPD with MRONJ. In addition, we performed a systematic literature review to identify all cases of MTX-LPD of the oral cavity, to investigate the characteristics of oral MTX-LPD.\n\nCase Report\nIn July 2015, an 81-year-old Japanese woman was referred to the Department of Oral Surgery at Kyushu University Hospital for the evaluation of upper left mandible pain. In 2009, the patient was diagnosed with RA based on the findings of bone destruction and swelling at her wrists and a positive serum test for rheumatoid factor. She had been taking BP (BonalonⓇ; 35 mg/week) and prednisolone (PrednisolonⓇ; 5 mg/day) for 7 years and MTX (MetolateⓇ; 8 mg/week) for 4 years. In April 2015, she fell while walking on stairs and noticed slight bleeding near her left first molar. Two weeks earlier she visited another dentist due to continuous pain of the left maxillary gingiva that had persisted for 2 months. The dentist suspected MRONJ based on the exposure of the maxillary bone.\n\nOur initial examination revealed an ulcer with induration on the buccal gingiva, near the upper left molar, which was mobile (Fig. 1A). Radiography showed left sinusitis and the loss of vertical bone near the upper left molars (Fig. 1B). These findings suggested gingival carcinoma or lymphoma. A cytological analysis of the ulcerative gingiva revealed class III cytology accompanied by numerous atypical lymphocytes; however, these findings were not conclusive for malignancy. The results of serological tests were unremarkable; however, the patient's C-reactive protein concentration was slightly elevated (0.64 mg/dL). Coronal computed tomography revealed a lesion arising from the upper left second premolar to the left sinus and the destruction of the buccal cortical bone in the left posterior maxilla (Fig. 2A). 18Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) was performed to evaluate the extent of the primary lesion, the status of the regional lymph nodes, and the possibility of distant metastasis. The images showed the abnormal accumulation of FDG in the left upper maxilla and sinus (maximum standardized uptake value, 4.94) and no accumulation in several systemic lymph nodes or other lesions (Fig. 2B). These findings indicated that the lesion was malignant or another type of tumor. She was immediately referred to the hematology department of our hospital and an incisional biopsy of the upper left region was performed. Immunophenotyping of the upper left gingiva gated by CD45+ cells yielded the following findings: CD3+ CD20-, 48.3%; CD3- CD20+, 14.6%; natural killer cells, 30.5%; CD19+, 17.7%; κ chain, 4.25%; and λ chain, 3.72%. These findings were not conclusive for a diagnosis of any type of malignant lymphoma. A pathological analysis showed the infiltration of numerous lymphocytes and the diffuse proliferation of medium- to large-sized atypical lymphoid cells with large nuclei and clumped chromatin. Moreover, an immunohistochemical analysis revealed extensive lymphocytic infiltration. The cells were mostly B cells (positive for CD20 and CD79a); however a few T cells were found to be CD3-positive. The additional performance of in situ hybridization to detect EBV-encoded RNA (15) showed the strong infiltration of EBV-positive atypical lymphoid cells (Fig. 3). In sum, these findings confirmed a diagnosis of EBV-positive diffuse large B-cell lymphoma (DLBCL). Based on the pathological and clinical findings, the patient was diagnosed with MTX-LPD, and MTX therapy was immediately stopped (Fig. 4A-a). To control RA, the patient was treated with prednisolone (3 mg/day). We continued to monitor the patient carefully during the initial 2-week cessation of MTX. The exposed bone was rinsed three times a week with 0.05% glucuronic acid chlorhexidine solution, and the necrotic gingiva and induration gradually disappeared (Fig. 4A-b). At four months after the withdrawal of MTX and rinsing with glucuronic acid chlorhexidine solution, the upper left molars were easily extracted, along with the surrounding floating bone (Fig. 4A-c). The necrotic and indurated tissue had disappeared, and no other adverse events were noted (Fig. 4A-d). CT images obtained at 4 and 7 months after the withdrawal of MTX showed the improvement of the left sinusitis and the absence of inflammation or floating bone in the maxilla (Fig. 4B). No inflammation was observed near the upper left gingiva during this period, and the patient did not require antibiotic treatment. There was no recurrence of MTX-LPD or extra-nodal lymphoma, and her RA remained well controlled at 1 year after the discontinuation of MTX treatment.\n\nFigure 1. A photograph and photoradiograph obtained at the first examination. (A) The exposure of the buccal and palate bone, and the buccal root of the molars were noted (mirror reflection). The upper-left first and second molars showed deflection. (B) The left sinus had a cloudy appearance (yellow arrowhead).\n\nFigure 2. Computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET). (A) CT revealed a mass around the upper-left maxilla. (B) FDG-PET indicated abnormal accumulation in the upper-left gingiva.\n\nFigure 3. The histological and immunohistochemical findings of the upper-left gingiva. Hematoxylin and Eosin staining (a). Immunohistochemical staining for CD20 (b), CD79a (c), CD3 (d), and Epstein-Barr encoding region (EBER) (e). Scale bars: 100 μm.\n\nFigure 4. Photographs and photoradiographs obtained after the withdrawal of methotrexate (MTX). (A) Photographs of the upper-left maxilla at 0 days (a), 2 weeks (b), 4 months (c), and 7 months (d). All of the photographs show mirror reflections. (B) CT images obtained after the withdrawal of MTX for 4 months (a, b) and 7 months (c, d).\n\nDiscussion\nEvidence from numerous reports indicates that the risk of LPD in RA (RA-LPD) patients is 2.0-5.5 times that of the general population (16). The underlying mechanism is unclear; however, patients with RA have persistent immunological abnormalities that may lead to clonal selection, which can result in the malignant transformation of B cells, the decreased apoptosis of infected B cells, reduced natural killer cell activity, the proliferation of latent EBV infection, and direct oncogenic action. All of these conditions may be potentiated by immunomodulation therapies. The number of reported LPD cases has been increasing among patients with RA receiving MTX, a condition referred to as MTX-LPD (8). The characteristics of MTX-LPD are as follows: (1) the most frequent subtype of MTX-LPD is DLBCL rather than Hodgkin lymphoma or Hodgkin disease-like lymphoma, (2) the frequency of EBV-positive case is higher in MTX-LPD than in RA-LPD or age-related LPD, (3) the possibility of improvement is high (20-60%), but only when MTX is withdrawn for several weeks, (4) the frequency of extra-nodal lymphoma is higher in MTX-LPD cases than in RA-LPD or age-related LPD cases, and (5) the duration to the outcome is shorter in patients with MTX-LPD than in those with RA-LPD (17,18). In approximately 40-50% of cases, MTX-LPD develops at extra-nodal sites, such as the skin, lung, liver, gastrointestinal tract, and kidney (8).\n\nA review of the literature revealed only 19 cases of oral MTX-LPD, including our 3 cases (Table 1) (7,19-30). At the time of the diagnosis of MTX-LPD, the mean age of the patients was 71.1 years (range, 44-87 years) and the male-to-female ratio was 4:15 (the male-to-female ratio in RA was 1:4). The mean duration of MTX treatment was 6.6 years (range, 0.1-20 years). The frequency of bone exposure and DLBCL was 56.2% (9/16), the frequency of EBV positivity was 100.0% (13/13), and MTX-LPD resolved in 80.0% (12/15) of patients after the discontinuation of MTX. The data on the mean age, sex ratio, and the duration of MTX treatment were similar to those of previous reports on oral MTX-LPD. In contrast, the frequency of DLBCL and EBV-positivity in the patients with oral MTX-LPD were higher in comparison to previous reports on non-oral MTX-LPD, as summarized in Table 2 (6,21,24,31). Some reports have suggested that spontaneous remission occurs due to the withdrawal of MTX and noted an association between EBV positivity and the spontaneous remission of MTX-LPD (32). The initial symptoms of oral MTX-LPD included ulcer (80.0%, 12/15) and swelling (20.0%, 3/15), and the main sites affected included the gingiva (66.7%, 12/18), the hard palate (11.1%, 2/18) and the buccal mucosa (11.1%, 2/18). Other regions of the oral cavity, including the tongue, soft palate, sinus, and lip, can also be target organs because EBV in the head and neck region, including the pharynx and the salivary glands, generally remains dormant. Dentists and clinicians should bear in mind that MTX-LPD can be observed in any lesion.\n\nTable 1. Clinicopathological Findings of 19 Cases with Oral Methotrexate-related Lymphoproligeractive Disorders (MTX-LPD).\n\nNo.\tAge\tSex\tLesion\tComplaining\tMTX intake (y)\tHistology\tEBV\tBP intake (y)\tBone Exposure\tMTX withdrawal\tRecurrence\tChemotherapy\tReference\t\n1.\t72\tF\tgingiva\tulcer\tNA\tpoly-B cell lymphoma\t+\tNA\t+\t+\t-\t-\t(19)\t\n2.\t69\tF\tgingiva\tulcer\tNA\tWegener’s lymphoma\tNA\tNA\t+\t+\t-\t-\t(19)\t\n3.\t73\tF\toral cavity\tNA\t2\tperipheral T cell lymphoma\tNA\t-\t-\t+\t-\t-\t(21)\t\n4.\t73\tF\toral cavity\tNA\t2\tDLBCL\tLMP-1\t-\t+\t+\t-\t-\t(20)\t\n5.\t70\tF\tpalate\tulcer\t6\tDLBCL\tEBNA2\t-\t-\t+\t-\t-\t(7)\t\n6.\t69\tF\tgingiva\tNA\tNA\tHodgkin\tLMP-1\t-\tNA\t+\tNA\tNA\t(22)\t\n7.\t80\tM\ttongue\tulcer\tNA\tNA\tNA\tNA\t-\tNA\tNA\tNA\t(30)\t\n8.\t76\tF\tgingiva\tulcer, bleeding\t10\tDLBCL\tEBER\t-\t-\t+\t+\tR-THP-COP\t(24)\t\n9.\t67\tF\tpalate\tulcer\t9\tDLBCL\tEBER\t9\t+\t+\t-\t-\t(25)\t\n10.\t75\tF\tgingiva\tswelling\t5\tDLBCL\tEBER\tNA\t+\t+\t+\tR-CHOP\t(26)\t\n11.\t60\tM\tgingiva\tswelling\t20\tDLBCL\tEBER\t-\t+\t+\t-\t-\t(27)\t\n12.\t71\tF\tbuccal mucosa\tulcer\t0.1\tNA\tNA\t+\t-\t+\t-\t-\t(28)\t\n13.\t87\tF\tbuccal mucosa\tulcer\t2\tNA\tNA\t+\t-\t+\t-\t-\t(28)\t\n14.\t66\tF\tgingiva\tulcer\t3\tDLBCL\tNA\t8M\t+\t+\t-\t-\t(29)\t\n15.\t76\tF\tgingiva\tNA\tNA\tHodgkin\tLMP-1\tNA\tNA\t+\tNA\tNA\t(23)\t\n16.\t67\tM\tpalate\tNA\tNA\tNA\tLMP-1\tNA\tNA\t+\tNA\tNA\t(23)\t\n17.\t81\tF\tgingiva\tulcer\t4\tDLBCL\tEBER\t7\t+\t+\t-\t-\tThis case\t\n18.\t71\tF\tgingiva\tulcer\tNA\tBL\tEBER\t+\t+\t+\t-\t-\tour cases\t\n19.\t77\tF\tgingiva\tulcer\t12\tDLBCL\tEBER\t+\t+\t+\t+\tR-CHOP\t\nMTX: methotrexate, EBV: Epstein-Barr Virus, DLBCL: diffuse large B-cell lymphoma, LMP: latent infection membrane protein, EBNA: EBV nuclear antigen, EBER: Epstein-Barr encording region, R-THP-COP: rituximab, pinorubin, oncovin, endoxan, and prednisolone, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, +: positive, −: negative, NA: not available\n\nTable 2. Comparison of Clinicopathological Findings between Oral and Non-oral MTX-LPD.\n\n\tOral MTX (n=17)\tNon-oral MTX (n=52)\t\nMean age (years)\t71.1\t63.0-69.0\t\nSex (male : female)\t4:13\t20:32\t\nAffected regions\tgingiva, palate, buccal mucosa, tongue\tlymph node, spleen, lung, skin, liver, pleura, kidney, small bowel, breast, neck, thymus, stomach, heart\t\nDuration of MTX treatment (years)\t6.6\t3.1-5.8\t\nDLBCL (%)\t56.2\t30.8-55.3\t\nEBV-positive (%)\t100\t50.0-62.8\t\nReference\tTable 1\t(7), (21), (32)\t\nMTX-LPD: methotrexate- related lymphoproliferative disorder, DLBCL: diffuse large B-cell lymphoma, EBV: Epstein-Barr virus\n\nOur patient had been treated with BPs for 9 years and MTX for 4 years. A diminished CTL function caused by the immunosuppressive effect of MTX permits the reactivation of EBV and the monoclonal proliferation of EBV-infected B cells in the buccal gingiva. Since the gingiva has a unique environment, characterized by its direct contact with the alveolar bone through the periodontal pocket, patients with LPD affecting the cervical gingiva are prone to develop bone exposure, and those who are treated with BPs may subsequently develop necrosis of the alveolar bone.\n\nRecently, EBV-positive mucocutaneous ulcer (EBV-MCU) was proposed as a novel clinical entity that presents as mucocutaneous ulcers of the oropharynx, gastrointestinal tract, or skin, which are caused by latent EBV infection. Iatrogenic immunosuppression for autoimmune disease and age-related immunosenescence have been implicated as risk factors (30).The clinical conditions of this case might be close to those of EBV-MCU.\n\nThe presence of ulcer and adjacent bone exposure in the gingiva complicated the initial diagnosis because the common manifestations of MRONJ include ulcer, swelling, fistula, abscess, and bone exposure. However, our patient also exhibited the progression of ulceration and induration. We therefore performed an incisional biopsy as soon as we suspected malignancy or another tumor. After the diagnosis was confirmed, MRONJ was treated by daily cleaning around the site of bone necrosis with glucuronic acid chlorhexidine solution. After this, the floating necrotic bone and molars gradually resolved. The gingival ulceration and induration resolved in association with bone removal. No guidelines have been established for the treatment of MTX-LPD; however, pathological and immunological examinations are necessary in the selection of treatment.\n\nWe described a case of MTX-LPD with severe MRONJ and the effects of treatment after MTX withdrawal. Many previous case reports have described gingival ulcers or swelling near the sites of osteonecrosis; however, no previous reports have described the treatment of MRONJ or differentiation between MRONJ and MTX-LPD with MRONJ. The present case and the associated review of the literature on oral MTX-LPD suggest that oral MTX-LPD will continue to be a concern because RA patients are increasingly treated with MTX and BPs. Despite the risk of severe adverse effects, MTX is the treatment of choice for RA. Clinicians should bear in mind that oral MTX-LPD is occasionally complicated by MRONJ, and that a pathological examination (e.g., an incisional biopsy and immunohistological examination) is required for the final diagnosis. Additionally, close collaboration with internists or hematologists should be considered when developing a treatment plan.\n\n\nWritten informed consent was obtained from the patient for publication of this report and the use of any accompanying images.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis work was supported in part by grants from the “Shiinoki Foundation (Kyushu University)”.\n==== Refs\n1. \nLiote F , Pertuiset E , Cochand-Priollet B , et al \nMethotrexate related B lymphoproliferative disease in a patient with rheumatoid arthritis. Role of Epstein-Barr virus infection . J Rheumatol \n22 : 1174 -1178 , 1995 .7674250 \n2. \nKamel OW , van de Rijn M , LeBrun DP , Weiss LM , Warnke RA , Dorfman RF \nLymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression . 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Am J Pathol \n139 : 1259 -1265 , 1991 .1661073\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(4)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "Epstein-Barr virus; lymphoma; medication-related osteonecrosis of the jaw; methotrexate-related lymphoproliferative disorder; rheumatoid arthritis", "medline_ta": "Intern Med", "mesh_terms": "D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D005260:Female; D006801:Humans; D007568:Jaw; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D010020:Osteonecrosis; D012720:Severity of Illness Index", "nlm_unique_id": "9204241", "other_id": null, "pages": "575-581", "pmc": null, "pmid": "29225245", "pubdate": "2018-02-15", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "24498893;11054684;18167381;8026822;16859835;23560463;17117491;24400722;24811204;25234529;26608686;18461290;25302816;18670155;25834572;23728424;25319961;8656264;17307580;1661073;18571037;20676828;20154586;7674250;9044507;26468825;24133604;15953917;10451061", "title": "Oral Methotrexate-related Lymphoproliferative Disease Presenting with Severe Osteonecrosis of the Jaw: A Case Report and Literature Review.", "title_normalized": "oral methotrexate related lymphoproliferative disease presenting with severe osteonecrosis of the jaw a case report and literature review" }	[ { "companynumb": "JP-CIPLA LTD.-2018JP11601", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "35 MG, PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "35", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus associated lymphoproliferative disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FURUKAWA S, OOBU K, MORIYAMA M, KAWANO S, SAKO S, HAYASHIDA JN ET AL. ORAL METHOTREXATE-RELATED LYMPHOPROLIFERATIVE DISEASE PRESENTING WITH SEVERE OSTEONECROSIS OF THE JAW: A CASE REPORT AND LITERATURE REVIEW. INTERNAL MEDICINE. 2018?57(4):575 TO 581", "literaturereference_normalized": "oral methotrexate related lymphoproliferative disease presenting with severe osteonecrosis of the jaw a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14645712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "We report a case of a 60-year-old man who was referred to a palliative care clinic with monoclonal gammopathy of undetermined significance (MGUS)-associated neuropathy, responding to a therapeutic trial of warfarin. Electromyography showed distal symmetric sensory axonal neuropathy. The patient reported having had improvement of his neuropathic symptoms while taking warfarin postoperatively for thromboprophylaxis 1 year prior, and recurrence of his symptoms after the warfarin was discontinued. The patient was rechallenged with a trial of warfarin, targeting an international normalised ratio of 1.5-2.0. His pain scores decreased from 5/10 to 3/10 at 1 month and symptom improvement was maintained through 24 months of follow-up. Warfarin had a remarkable impact on our patient's symptoms and quality of life. The mechanisms mediating the symptomatic benefit with warfarin are unclear; however, a placebo effect is unlikely. Further studies may help guide the use of warfarin for MGUS-associated neuropathy.", "affiliations": "Division of Palliative Care, Greenville Health System, Greenville, South Carolina, USA.;Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University Health System, Richmond, Virginia, USA.;Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University Health System, Richmond, Virginia, USA.;Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University Health System, Richmond, Virginia, USA.", "authors": "Henry Gomez\|Teny\|T\|;Holkova\|Beata\|B\|;Noreika\|Danielle\|D\|;Del Fabbro\|Egidio\|E\|", "chemical_list": "D000925:Anticoagulants; D014859:Warfarin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2016()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000925:Anticoagulants; D006801:Humans; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance; D010523:Peripheral Nervous System Diseases; D016896:Treatment Outcome; D014859:Warfarin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "27317760", "pubdate": "2016-06-17", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12780789;18796075;7820574;8894407;8909434;9040714;1379409;11911978;23114670;12473754;645746;10540371;10639604;6253529;8383189;18559977;17253554;20175830;16571879;10209166;11325029;23255326;9406596;22516728", "title": "Warfarin improves neuropathy in monoclonal gammopathy of undetermined significance.", "title_normalized": "warfarin improves neuropathy in monoclonal gammopathy of undetermined significance" }	[ { "companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2016GMK024021", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077662", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077662", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "300 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GOMEZ TH, HOLKOVA B, NOREIKA D, DEL FABBRO E.. WARFARIN IMPROVES NEUROPATHY IN MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE.. BMJ CASE REPORTS. 2016;215518", "literaturereference_normalized": "warfarin improves neuropathy in monoclonal gammopathy of undetermined significance", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160912", "receivedate": "20160912", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12735665, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]
{ "abstract": "BACKGROUND\nThe safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown.\n\n\nMETHODS\nWe describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen.\n\n\nCONCLUSIONS\nBecause of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.", "affiliations": "Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Department of Pathology, Faculty of Medicine, Saga University Hospital, Saga, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan. [email protected].", "authors": "Hirakawa\|Haruki\|H\|;Nakashima\|Chiho\|C\|;Nakamura\|Tomomi\|T\|;Masuda\|Masanori\|M\|;Funakoshi\|Taro\|T\|;Nakagawa\|Shunsaku\|S\|;Horimatsu\|Takahiro\|T\|;Matsubara\|Kazuo\|K\|;Muto\|Manabu\|M\|;Kimura\|Shinya\|S\|;Sueoka-Aragane\|Naoko\|N\|", "chemical_list": "D000970:Antineoplastic Agents; D005047:Etoposide; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1186/s13256-017-1213-7", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 121310.1186/s13256-017-1213-7Case ReportChemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report Hirakawa Haruki [email protected] 1Nakashima Chiho [email protected] 1Nakamura Tomomi [email protected] 1Masuda Masanori [email protected] 2Funakoshi Taro [email protected] 3Nakagawa Shunsaku [email protected] 4Horimatsu Takahiro [email protected] 3Matsubara Kazuo [email protected] 4Muto Manabu [email protected] 3Kimura Shinya [email protected] 1Sueoka-Aragane Naoko [email protected] 11 0000 0001 1172 4459grid.412339.eDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan 2 grid.416518.fDepartment of Pathology, Faculty of Medicine, Saga University Hospital, Saga, Japan 3 0000 0004 0372 2033grid.258799.8Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4 0000 0004 0531 2775grid.411217.0Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan 16 2 2017 16 2 2017 2017 11 434 10 2016 17 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown.\n\nCase presentation\nWe describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen.\n\nConclusions\nBecause of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.\n\nKeywords\nMediastinal yolk sac tumorHemodialysisRenal insufficiencyCisplatinPharmacokineticsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nGerm cell tumors of extragonadal origin have been reported to make up from 1 to 5% of all germ cell tumors. The most common site is the mediastinum, constituting 50 to 70% [1, 2]. In general, germ cell tumors are sensitive to platinum-based chemotherapy and patients have a favorable prognosis. However, response of mediastinal non-seminomatous germ cell tumors to therapy is less than favorable, so these tumors have been classified into the poor prognosis group [3, 4]. It has been reported that 40 to 54% of patients with mediastinal non-seminomatous germ cell tumor treated with platinum-based chemotherapy followed by surgical resection achieved long-term disease-free survival, but patients who relapsed after initial treatment experienced dismal outcomes with only 10% long-term survival [5–7]. Therefore, it is important to accomplish successful initial chemotherapy with an adequate dose.\n\nRecently, the number of patients with end-stage renal failure undergoing hemodialysis (HD) is increasing, and patients undergoing HD are potentially at high risk of cancer [8]. However, the safety and efficacy of chemotherapy for patients undergoing concomitant HD have not been fully established and optimal doses of anti-cancer drugs and best timing of HD remains unclear. Many patients with cancer undergoing HD might be under-treated because the pharmacokinetics (PK) of anti-cancer drugs in such patients remains unknown and severe adverse effects are feared. However, chemosensitive cancers such as germ cell tumors treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect.\n\nIn this article, we report the case of a patient with mediastinal yolk sac tumor who was successfully treated with cisplatin and etoposide while concomitantly undergoing HD. We carried out a PK analysis of cisplatin as part of a multicenter study and carefully considered the relationship between adverse effects and blood concentration of cisplatin.\n\nCase presentation\nA 31-year-old Japanese man was referred to our hospital with renal dysfunction in April 2014. He had a history of hypertension, hyperuricemia, and pituitary dwarfism, but had not taken any medications. He was 159.4 cm in height and 42.6 kg in weight (body surface area 1.398 m2). Initial blood tests showed anemia and renal dysfunction: blood urea nitrogen (BUN) 64.6 mg/dl, creatinine (Cr) 5.66 mg/dl. A chest X-ray performed to evaluate cardiomegaly revealed a mediastinal tumor in his right thorax; a computed tomography (CT) scan confirmed the mass to be a well-defined, homogeneous solid tumor (53×35 mm) in his anterior mediastinum (Fig. 1). An additional blood examination showed a high level, 322.6 ng/ml, of alpha-fetoprotein (AFP, normal <9 ng/ml), but his beta-human chorionic gonadotropin (β-hCG) level was within normal range. A CT-guided biopsy of the mediastinal tumor showed the presence of tumor cells with mixed sinusoidal-like, cystic, and papillary structures (Fig. 2a) and Schiller–Duval body (Fig. 2b), which was positive by immunohistochemistry (IHC) for cytokeratin (CK) AE1/AE3 and AFP, and negative for placental alkaline phosphatase (PLAP), β-hCG, and CD30 (Fig. 2c, d), resulting in a diagnosis of primary mediastinal yolk sac tumor. Because of the complication of end-stage renal insufficiency, surgery was selected as the first treatment; following surgery, his AFP level decreased to the normal range. Subsequently, chemotherapy with cisplatin (10 mg/m2) and etoposide (60 mg/m2) was conducted daily from day 1 through to day 5. HD was started 1 hour after infusions of these agents. Appendicitis with grade 4 neutropenia occurred, so an appendectomy was performed after the first cycle. In addition, grade 3 anemia and grade 4 neutropenia appeared under prophylactic treatment with granulocyte-colony stimulating factor (G-CSF). Because severe hematological toxicities occurred, we conducted chemotherapy without dose escalation on the second cycle. In contrast to the first cycle, toxicities were admissible with 10 mg/m2 cisplatin and 60 mg/m2 etoposide in the second cycle. To elevate the dose intensity, the doses were escalated from the third to the fifth cycles: cisplatin to 15 mg/m2 and etoposide to 75 mg/m2. Grade 4 neutropenia and thrombocytopenia as well as grade 3 anemia were sustained over 7 days in spite of prophylactic treatment with G-CSF. After five cycles of chemotherapy, his AFP level remained in the normal range and there has been no recurrence for 1 year.Fig. 1 Computed tomography scan confirms a solid tumor (53×35 mm) in the anterior mediastinum (arrow)\n\n\nFig. 2 Pathological findings of computed tomography-guided biopsy specimen. a Tumor cells with mixed sinusoidal-like, cystic, and papillary structures were observed (hematoxylin and eosin staining, ×20). b Schiller–Duval body was highlighted with white arrow (hematoxylin and eosin staining, ×100). Immunohistochemical staining is positive for cytokeratin AE1/AE3 (×200) (c) and alpha-fetoprotein (d) (×200)\n\n\n\n\nDuring the third and fourth cycles, free cisplatin blood concentrations were measured as part of a multicenter study. Venous blood samples were collected five times each day: (1) before cisplatin infusion, (2) immediately after infusion, (3) before HD, (4) after HD, and (5) 4 hours after HD on days 1 to 5. In addition, blood was collected before HD on day 8 once in each course (Fig. 3). The time-concentration curve in the third cycle is shown in Fig. 4. Our patient was administered 15 mg/m2 cisplatin, and maximum concentration (Cmax) of free cisplatin was 0.8 to 0.9 μg/mL. Just before treatment with cisplatin, the concentration had not recovered to the level observed after the previous HD. The concentration before infusion of cisplatin gradually increased each day during the 5 days of treatment, and this phenomenon was observed until 8 days after the start of chemotherapy. During the fourth cycle, chemotherapy was administered using the same doses used in the third cycle, and PK was similar to that of the third cycle.Fig. 3 Schedule of chemotherapy, hemodialysis, and blood sampling. In the third and fourth chemotherapy cycles, cisplatin (15 mg/m2) and etoposide (75 mg/m2) was conducted daily from day 1 through to day 5. Hemodialysis was started 1 hour after infusions of these agents. Venous blood samples were collected five times each day: (1) before cisplatin infusion, (2) immediately after infusion, (3) before hemodialysis, (4) after hemodialysis, and (5) 4 hours after hemodialysis on days 1 to 5. In addition, blood was collected (6) before hemodialysis on day 8 once in each course. CDDP cisplatin, ETP etoposide, HD hemodialysis\n\n\nFig. 4 Free cisplatin concentration analysis. The solid and dotted lines show plasma free cisplatin concentration in the third and fourth chemotherapy cycles, respectively. White arrows indicate cisplatin (15 mg/m2) infusions and black two-headed arrows indicate hemodialysis during days 1 to 5. HD hemodialysis\n\n\n\n\nDiscussion\nIn the International Germ Cell Consensus Classification (IGCCC), primary mediastinal yolk sac tumor is classified into the poor prognosis group, and standard treatment consists of induction chemotherapy such as BEP (bleomycin, etoposide, and cisplatin) or VIP (ifosfamide, etoposide, and cisplatin) regimens followed by radical operation [4]. In our case, it was considered likely that standard chemotherapy would not be efficacious because of end-stage renal insufficiency, so surgery was selected as the first treatment so as not to miss the opportunity for complete tumor resection. In addition, bleomycin and active metabolite of ifosfamide are known not to be sufficiently removed by HD, resulting in enhanced toxicities such as pulmonary fibrosis, disturbance of consciousness, and convulsions [9–14]. Therefore, we selected combination chemotherapy with cisplatin and etoposide, and doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through 5 according to previous reports, and the doses were subsequently escalated to 75% with both agents [14]. However, the rationale for using these dosages, especially that of cisplatin, has not been elucidated because of a paucity of PK studies involving patients with HD. Froehner et al. reported that they started the treatment from 50% reduction of cisplatin according to guidelines on testicular cancer, and then escalated to 100% of standard dose after monitoring adverse effects [14].\n\nIn this case, we obtained PK results for cisplatin during cycles 3 and 4 in cooperation with Kyoto University. The findings are as follows, compared with patients with normal renal function administered 100% standard doses of cisplatin [15]: (1) the Cmax of free cisplatin was higher, and (2) concentration gradually increased after HD up to the subsequent infusion of cisplatin (Fig. 4). The higher Cmax might be related to our patient’s low volume of distribution caused by pituitary dwarfism rather than renal insufficiency. Immediately after HD, the concentrations were lower, equivalent to those in patients with normal renal function based on previous reports [15]. However, his free cisplatin concentration rose 4 hours after HD, and gradual accumulation of free cisplatin was observed up until the subsequent treatment with cisplatin. Pronounced elevation of free cisplatin concentration may be due to redistribution from peripheral tissues and reduced excretion of free cisplatin, resulting in an elevated area under the curve (AUC) of free cisplatin leading to severe hematological toxicity [15–18]. Although nephrotoxicity has not been thought to be a limitation in HD patients, dose-related adverse effects are often observed [19], and dose reduction is inevitable just as in our case. Because of the altered PK pharmacodynamics (PD) status of patients with renal dysfunction undergoing HD, determination of cisplatin dosage should be based on monitored concentration to conduct effective and safe chemotherapy.\n\nConclusions\nMalignancies sensitive to chemotherapy require careful maintenance of dose intensity, but this should be performed safely. PK analysis is deemed to be useful for appropriate chemotherapy in patients undergoing HD. Additional evidence from other similar patients is needed to establish suitable chemotherapy regimens for patients with concomitant renal insufficiency.\n\nAbbreviations\nAFPAlpha-fetoprotein\n\nAUCArea under the curve\n\nBEPBleomycin, etoposide, and cisplatin\n\nβ-hCGBeta-human chorionic gonadotropin\n\nBUNBlood urea nitrogen\n\nCKCytokeratin\n\nCmaxMaximum concentration\n\nCrCreatinine\n\nCTComputed tomography\n\nG-CSFGranulocyte-colony stimulating factor\n\nHDHemodialysis\n\nIGCCCInternational Germ Cell Consensus Classification\n\nIHCImmunohistochemistry\n\nPDPharmacodynamics\n\nPKPharmacokinetics\n\nPLAPPlacental alkaline phosphatase\n\nVIPIfosfamide, etoposide, and cisplatin\n\nAcknowledgements\nWe wish to thank our patient and his parents for consenting to the publication of this case report.\n\nFunding\nThere is no financial support for this case report.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nHH, CN, TN, SK, and NSA contributed to patient treatment and collection of venous blood samples for PK PD analysis. MMa contributed to pathological diagnosis. TF, SN, TH, KM, and MMu contributed measurement of free cisplatin blood concentration and PK PD analysis. All authors read and approved the final manuscript. \n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nThe protocol of this multicenter study was approved by the Clinical Research Ethics Committees of Saga University. This patient gave informed consent for blood collection and PK PD analysis according to the Declaration of Helsinki.\n==== Refs\nReferences\n1. McKenney JK Heerema-McKenney A Rouse RV Extragonadal germ cell tumors: a review with emphasis on pathologic features, clinical prognostic variables, and differential diagnostic considerations Adv Anat Pathol. 2007 14 69 92 10.1097/PAP.0b013e31803240e6 17471115 \n2. Dehner LP Germ cell tumors of the mediastinum. Germ cell tumors of the mediastinum Semin Diagn Pathol 1990 7 266 84 2178277 \n3. International Germ Cell Cancer Collaborative Group International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers J Clin Oncol 1997 15 594 603 9053482 \n4. Schmoll HJ Souchon R Krege S Albers P Beyer J Kollmannsberger C European Germ Cell Cancer Consensus Group European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG) Ann Oncol 2004 15 1377 99 10.1093/annonc/mdh301 15319245 \n5. Albany C Einhorn LH Extragonadal germ cell tumors: clinical presentation and management Curr Opin Oncol. 2013 25 261 5 23422328 \n6. Bokemeyer C Nichols CR Droz JP Schmoll HJ Horwich A Gerl A Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis J Clin Oncol. 2002 20 1864 73 10.1200/JCO.2002.07.062 11919246 \n7. Rodney AJ Tannir NM Siefker-Radtke AO Liu P Walsh GL Millikan RE Survival outcomes for men with mediastinal germ-cell tumors: the University of Texas M. D. Anderson Cancer Center experience Urol Oncol 2012 30 879 85 10.1016/j.urolonc.2010.08.005 20933444 \n8. Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Cancer in patients on dialysis for end-stage renal disease: an international collaborative study Lancet. 1999 354 93 9 10.1016/S0140-6736(99)06154-1 10408483 \n9. Superfin D Iannucci AA Davies AM Commentary: Oncologic drugs in patients with organ dysfunction: a summary Oncologist. 2007 12 1070 83 10.1634/theoncologist.12-9-1070 17914077 \n10. Eneman JD Philips GK Cancer management in patients with end-stage renal disease Oncology (Williston Park) 2005 19 1199 214 16255135 \n11. Crooke ST Luft F Broughton A Strong J Casson K Einhorn L Bleomycin serum pharmacokinetics as determined by a radioimmunoassay and a microbiologic assay in a patient with compromised renal function Cancer. 1977 39 1430 4 10.1002/1097-0142(197704)39:4<1430::AID-CNCR2820390412>3.0.CO;2-V 66973 \n12. Tomita M Aoki Y Tanaka K Effect of haemodialysis on the pharmacokinetics of antineoplastic drugs Clin Pharmacokinet. 2004 43 515 27 10.2165/00003088-200443080-00002 15170366 \n13. Carlson L Goren MP Bush DA Griener JC Quigley R Tkaczewski I Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms’ tumor Cancer Chemother Pharmacol. 1998 41 140 6 10.1007/s002800050720 9443627 \n14. Froehner M Passauer J Schuler U Hakenberg OW Wirth MP Successful chemotherapy for advanced nonseminomatous germ-cell tumor in a patient undergoing chronic hemodialysis J Clin Oncol. 2007 10 1282 4 10.1200/JCO.2006.09.9549 \n15. Ikeda K Terashima M Kawamura H Takiyama I Koeda K Takagane A Pharmacokinetics of cisplatin in combined cisplatin and 5-fluorouracil therapy: a comparative study of three different schedules of cisplatin administration Jpn J Clin Oncol. 1998 28 168 75 10.1093/jjco/28.3.168 9614438 \n16. Yamada Y Ikuta Y Nosaka K Miyanari N Hayashi N Mitsuya H Successful treatment of Cisplatin overdose with plasma exchange Case Rep Med. 2010 2010 802312 20300587 \n17. Chu G Mantin R Shen YM Baskett G Sussman H Massive cisplatin overdose by accidental substitution for carboplatin Toxic Manag Cancer. 1993 72 3707 14 \n18. Schellens JH Ma J Planting AS van der Burg ME van Meerten E de Boer-Dennert M Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours Br J Cancer. 1996 73 1569 75 10.1038/bjc.1996.296 8664132 \n19. Janus N Thariat J Boulanger H Deray G Launay-Vacher V Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients Ann Oncol. 2010 21 1395 403 10.1093/annonc/mdp598 20118214\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "11(1)", "journal": "Journal of medical case reports", "keywords": "Cisplatin; Hemodialysis; Mediastinal yolk sac tumor; Pharmacokinetics; Renal insufficiency", "medline_ta": "J Med Case Rep", "mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018240:Endodermal Sinus Tumor; D005047:Etoposide; D006801:Humans; D008297:Male; D008479:Mediastinal Neoplasms; D008482:Mediastinum; D006435:Renal Dialysis; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101293382", "other_id": null, "pages": "43", "pmc": null, "pmid": "28202048", "pubdate": "2017-02-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9614438;9053482;17471115;17914077;2178277;10408483;16255135;66973;11919246;15170366;20933444;17401020;8664132;9443627;8252487;20300587;23422328;15319245;20118214", "title": "Chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report.", "title_normalized": "chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis a case report" }	[ { "companynumb": "JP-ACCORD-048843", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "074513", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSES ESCALATED FROM THE THIRD?TO THE FIFTH CYCLES: ETOPOSIDE TO 75MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "42.6", "reaction": [ { "reactionmeddrapt": "Appendicitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIRAKAWA H, NAKASHIMA C, NAKAMURA T, MASUDA M, FUNAKOSHI T, NAKAGAWA S, ET AL. CHEMOTHERAPY FOR PRIMARY MEDIASTINAL YOLK SAC TUMOR IN A PATIENT UNDERGOING CHRONIC HEMODIALYSIS: A CASE REPORT. J MED CASE REP. 2017 FEB 16;11(1):43.", "literaturereference_normalized": "chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170306", "receivedate": "20170306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13296968, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "At the extreme spectrum of consciousness during sleep, some patients with rare hypersomnias reported experiencing a specific night 'blackout' when sleeping, i.e., an absence of experiences or recall of them from sleep onset to offset. Thus, we explored through questionnaires the conscious experiences (dreaming experience, mind, self) during the night in 133 patients with idiopathic hypersomnia, 108 patients with narcolepsy, and 128 healthy controls. The night blackout was more frequent in idiopathic hypersomnia than in narcolepsy and control groups. Patients with idiopathic hypersomnia and frequent night amnesia had lower dream recall frequencies, and felt more often sleep as deep and mind as blank during the night. They had a higher proportion of slow wave sleep on their (retrospectively collected) sleep recordings than those without night blackout. This night blackout provides a new model for studying loss of consciousness during sleep, here as a contentless, selfless and timeless feeling upon awakening.", "affiliations": "Sorbonne University, Paris, France; Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France.;Sorbonne University, Paris, France.;Sorbonne University, Paris, France.;Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; National Reference Center on Narcolepsy and Rare Hypersomnias, France.;Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; National Reference Center on Narcolepsy and Rare Hypersomnias, France.;Sorbonne University, Paris, France; Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; National Reference Center on Narcolepsy and Rare Hypersomnias, France. Electronic address: [email protected].", "authors": "Chabani\|Emma\|E\|;Vionnet\|Marie Charlotte\|MC\|;Beauté\|Romy\|R\|;Leu-Semenescu\|Smaranda\|S\|;Dodet\|Pauline\|P\|;Arnulf\|Isabelle\|I\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.concog.2020.102931", "fulltext": null, "fulltext_license": null, "issn_linking": "1053-8100", "issue": "81()", "journal": "Consciousness and cognition", "keywords": "Amnesia; Blackout; Consciousness; Hypersomnia; Narcolepsy; Non-dreamer; Self", "medline_ta": "Conscious Cogn", "mesh_terms": "D000328:Adult; D000647:Amnesia; D003243:Consciousness; D004325:Dreams; D004532:Ego; D005260:Female; D006801:Humans; D020177:Idiopathic Hypersomnia; D008297:Male; D009290:Narcolepsy; D000077310:Sleep, Slow-Wave; D055815:Young Adult", "nlm_unique_id": "9303140", "other_id": null, "pages": "102931", "pmc": null, "pmid": "32339976", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Blackout of my nights: Contentless, timeless and selfless report from the night in patients with central hypersomnias.", "title_normalized": "blackout of my nights contentless timeless and selfless report from the night in patients with central hypersomnias" }	[ { "companynumb": "FR-JAZZ-2020-FR-007133", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SODIUM OXYBATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NARCOLEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XYREM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHABANI E, VIONNET MC, BEAUTE R, LEU?SEMENESCU S, DODET P, ARNULF I.. BLACKOUT OF MY NIGHTS: CONTENTLESS, TIMELESS AND SELFLESS REPORT FROM THE NIGHT IN PATIENTS WITH CENTRAL HYPERSOMNIAS. CONSCIOUSNESS AND COGNITION. 2020?81", "literaturereference_normalized": "blackout of my nights contentless timeless and selfless report from the night in patients with central hypersomnias", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200820", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18177987, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "FR-JAZZ-2020-FR-007111", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SODIUM OXYBATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XYREM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHABANI E, VIONNET MC, BEAUTE R, LEU?SEMENESCU S, DODET P, ARNULF I.. BLACKOUT OF MY NIGHTS: CONTENTLESS, TIMELESS AND SELFLESS REPORT FROM THE NIGHT IN PATIENTS WITH CENTRAL HYPERSOMNIAS.. CONSCIOUSNESS AND COGNITION. 2020?81", "literaturereference_normalized": "blackout of my nights contentless timeless and selfless report from the night in patients with central hypersomnias", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200820", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18177756, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS.\n\n\n\nA 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective.\n\n\n\nThis case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.", "affiliations": "Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.;Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.;Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.;Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.", "authors": "Calder\|Genevieve L\|GL\|;Ward\|Glenn M\|GM\|;Sachithanandan\|Nirupa\|N\|;MacIsaac\|Richard J\|RJ\|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel", "country": "United States", "delete": false, "doi": "10.1210/clinem/dgz301", "fulltext": null, "fulltext_license": null, "issn_linking": "0021-972X", "issue": "105(4)", "journal": "The Journal of clinical endocrinology and metabolism", "keywords": "clopidogrel; hypoglycemia; insulin autoimmune syndrome", "medline_ta": "J Clin Endocrinol Metab", "mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D000077144:Clopidogrel; D006801:Humans; D007003:Hypoglycemia; D008297:Male; D017202:Myocardial Ischemia; D010975:Platelet Aggregation Inhibitors; D011379:Prognosis; D013577:Syndrome", "nlm_unique_id": "0375362", "other_id": null, "pages": null, "pmc": null, "pmid": "32182368", "pubdate": "2020-04-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Insulin Autoimmune Syndrome: A Case of Clopidogrel-induced Autoimmune Hypoglycemia.", "title_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia" }	[ { "companynumb": "AU-PRINSTON PHARMACEUTICAL INC.-2020PRN00106", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PERINDOPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERINDOPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NICORANDIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NICORANDIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "206376", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Insulin autoimmune syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CALDER GL, WARD GM, SACHITHANANDAN N, MACISAAC RJ.. INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL-INDUCED AUTOIMMUNE HYPOGLYCEMIA. 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INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL-INDUCED AUTOIMMUNE HYPOGLYCEMIA. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN [ACETYLSALICYLIC ACID]" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anti-insulin antibody increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperplasia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insulin C-peptide increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insulin autoimmune syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood proinsulin increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood insulin increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CALDER GL, WARD GM, SACHITHANANDAN N, MACISAAC RJ.. INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL-INDUCED AUTOIMMUNE HYPOGLYCEMIA. THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. 2020?10:1?4", "literaturereference_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20200411", "receivedate": "20200408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17645340, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-257121", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, 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INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL?INDUCED AUTOIMMUNE HYPOGLYCEMIA. J CLIN ENDOCRINOL METAB. 2020?APR? 105(4):996?999", "literaturereference_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20200817", "receivedate": "20200817", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18154515, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "AU-MYLANLABS-2020M1070693", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", 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"drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROSE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Insulin autoimmune syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperinsulinaemic hypoglycaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CALDER GL, WAR GM, SACHITHANANDAN N, MACISAA RJ. INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL?INDUCED AUTOIMMUNE HYPOGLYCEMIA. J?CLIN?ENDOCRINOL?METAB 2020?105(4):996?999.", "literaturereference_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18145793, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "Purulent pericarditis is a rare clinical entity in the modern antibiotic era. The most common portal of entry is thought to be direct extension from a primary lung source and is usually caused by Staphylococcus aureus, Streptococcus pneumoniae or Haemophilus influenzae We report the case of a man aged 69 years who presented with purulent pericarditis due to Enterococcus faecalis likely caused by haematogenous spread from a urinary tract source. Urgent pericardiocentesis was vital and restored his haemodynamic stability. He was treated for a total duration of 4 weeks with susceptible antibiotics. Echocardiography 3 weeks later showed persistent resolution of the pericardial effusion. This case shows that prompt diagnosis and drainage of the pericardial effusion are vital to achieve a positive outcome in purulent pericarditis. To the best of our knowledge, this is the first reported case of purulent pericarditis caused by E. faecalis from a urinary tract source.", "affiliations": "Department of Internal Medicine, Kansas University School of Medicine-Wichita, Wichita, Kansas, USA.;Department of Internal Medicine, Kansas University School of Medicine-Wichita, Wichita, Kansas, USA.;Department of Pulmonary and Critical Care Medicine, Kansas University School of Medicine-Wichita, Wichita, Kansas, USA.", "authors": "Nehme\|Fredy\|F\|http://orcid.org/0000-0001-6433-178X;Gitau\|Jane\|J\|;Liu\|Jing\|J\|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-219498", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D013293:Enterococcus faecalis; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D020519:Pericardiocentesis; D010493:Pericarditis; D014552:Urinary Tract Infections", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28298381", "pubdate": "2017-03-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10433600;10967149;1138554;15001332;17670671;19352300;8227835;930941", "title": "Purulent pericarditis as a complication of bacteraemic Enterococcus faecalis urinary tract infection.", "title_normalized": "purulent pericarditis as a complication of bacteraemic enterococcus faecalis urinary tract infection" }	[ { "companynumb": "US-PFIZER INC-2017254396", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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LIU J. PURULENT PERICARDITIS AS A COMPLICATION OF BACTERAEMIC ENTEROCOCCUS FAECALIS URINARY TRACT INFECTION. BMJ CASE REPORTS. 2017; ARTICLE NUMBER 219498.", "literaturereference_normalized": "purulent pericarditis as a complication of bacteraemic enterococcus faecalis urinary tract infection", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170616", "receivedate": "20170616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13658861, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" } ]
{ "abstract": "Bupropion inhibits the uptake of dopamine and norepinephrine. Clinical effects in overdose include seizure, status epilepticus, tachycardia, arrhythmias, and cardiogenic shock. We report two cases of severe bupropion toxicity resulting in refractory cardiogenic shock, cardiac arrest, and repeated seizures treated successfully. Patients with cardiovascular failure related to poisoning may particularly benefit from extracorporeal membrane oxygenation (ECMO). These are the first cases of bupropion toxicity treated with veno-arterial EMCO (VA-ECMO) in which bupropion toxicity is supported by confirmatory testing. Both cases demonstrate the effectiveness of VA-ECMO in poisoned patients with severe cardiogenic shock or cardiopulmonary failure.", "affiliations": "Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA. [email protected].;Department of Medical Toxicology, Banner University Medical Center Phoenix, 925 E. McDowell Road, 2nd Floor Medical Toxicology, Phoenix, AZ, 85006, USA.;Department of Medicine, Section of Critical Care, Banner University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medicine, Section of Critical Care, Banner University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medical Toxicology, Banner University Medical Center Phoenix, 925 E. McDowell Road, 2nd Floor Medical Toxicology, Phoenix, AZ, 85006, USA.", "authors": "Heise\|C William\|CW\|;Skolnik\|Aaron B\|AB\|;Raschke\|Robert A\|RA\|;Owen-Reece\|Huw\|H\|;Graeme\|Kimberlie A\|KA\|", "chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion", "country": "United States", "delete": false, "doi": "10.1007/s13181-016-0539-7", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "12(3)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": "Bupropion; Cardiogenic shock; ECMO; Extracorporeal membrane oxygenation; Overdose; Status epilepticus", "medline_ta": "J Med Toxicol", "mesh_terms": "D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation; D001130:Arizona; D016642:Bupropion; D003131:Combined Modality Therapy; D003865:Depressive Disorder, Major; D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D012131:Respiratory Insufficiency; D012720:Severity of Illness Index; D012770:Shock, Cardiogenic; D013226:Status Epilepticus; D013406:Suicide, Attempted; D062606:Tertiary Care Centers; D016896:Treatment Outcome", "nlm_unique_id": "101284598", "other_id": null, "pages": "301-4", "pmc": null, "pmid": "26856351", "pubdate": "2016-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19822628;16027765;23238774;18062140;8305956;22469751;12831424;22615675;10332532;26624241;19897080;23697460;21623902;16183450;17766009;3936237;25454073;7665537;25634667;22087681;21206256", "title": "Two Cases of Refractory Cardiogenic Shock Secondary to Bupropion Successfully Treated with Veno-Arterial Extracorporeal Membrane Oxygenation.", "title_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation" }	[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-116796", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "78866", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 TABS", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL. 2016;12:301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171003", "receivedate": "20171003", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14032367, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "PHHY2016US069164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, 60 TABLETS OF 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. JOURNAL OF MEDICAL TOXICOLOGY. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160519", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12385217, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-APOTEX-2016AP008517", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "076143", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60 TABLETS OF 150MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION.. J-MED-TOXICOL. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160530", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383847, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2016PRN00044", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60-150 MG TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12192948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-BAUSCH-BL-2016-004532", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WILLIAM H, SKOLNIK A, OWEN-REECE H, RASCHKE R, GRAEME K. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL. 2016 FEB 08?.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160302", "receivedate": "20160302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12138038, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-IMPAX LABORATORIES, INC-2016-IPXL-00430", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075914", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "60 TABS OF 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE EXTENDED-RELEASE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, REECE HO, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL. 2016;1-4", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160425", "receivedate": "20160425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12302248, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-EDGEMONT-2016EDG00008", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50-90 TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160321", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12195896, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-CIPLA LTD.-2016US23956", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG, LOADING DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, LOADING DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK, GREATER THAN 50 AS MANY AS 90", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL.. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13087656, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2016PRN00043", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50 TO 90 150-MG TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12192956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-MYLANLABS-2016M1020375", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "GREATER THAN 50, AND PERHAPS AS MANY AS 90, BUPROPION 150MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;:.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160518", "receivedate": "20160518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383509, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-EDGEMONT-2016EDG00009", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60-150 MG TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160321", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12195902, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-HERITAGE PHARMACEUTICALS-2016HTG00247", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "206975", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "9000 MG, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016;12(3):301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161010", "receivedate": "20161010", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12834202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-ZYDUS-011147", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201567", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "INGESTING 60 TABS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Pupil fixed" }, { "drugrecuraction": "Cardiogenic shock" }, { "drugrecuraction": "Status epilepticus" }, { "drugrecuraction": "Mydriasis" }, { "drugrecuraction": "Bradycardia" }, { "drugrecuraction": "Cardiac arrest" }, { "drugrecuraction": "Leukocytosis" }, { "drugrecuraction": "Cardiomyopathy" }, { "drugrecuraction": "Overdose" }, { "drugrecuraction": "Electrocardiogram QRS complex prolonged" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION/BUPROPION HYDROCHLORIDE" } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160524", "receivedate": "20160524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12396722, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016US066342", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, 90 TABLETS.", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. JOURNAL OF MEDICAL TOXICOLOGY. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160520", "receivedate": "20160520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12388942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-MYLANLABS-2016M1020376", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60 TABLETS OF 150MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;:.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160518", "receivedate": "20160518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383510, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-APOTEX-2016AP008514", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "076143", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "GREATER THAN 50, AND PERHAPS AS MANY AS 90", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION.. J-MED-TOXICOL. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160527", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383795, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-ZYDUS-011140", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201567", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Status epilepticus" }, { "drugrecuraction": "Leukocytosis" }, { "drugrecuraction": "Mydriasis" }, { "drugrecuraction": "Pulmonary oedema" }, { "drugrecuraction": "Cardiogenic shock" }, { "drugrecuraction": "Pupil fixed" }, { "drugrecuraction": "Pulmonary haemorrhage" }, { "drugrecuraction": "Pneumonia aspiration" }, { "drugrecuraction": "Overdose" }, { "drugrecuraction": "Cardiomyopathy acute" }, { "drugrecuraction": "Cardiac arrest" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION/BUPROPION HYDROCHLORIDE" } ], "patientagegroup": "4", "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Creatinine urine abnormal", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urine output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160524", "receivedate": "20160524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12396725, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-CIPLA LTD.-2016US23955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. 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TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160425", "receivedate": "20160425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12300941, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-116795", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "78866", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50, AND PERHAPS AS MANY AS 90, TABLET", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL. 2016;12:301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171003", "receivedate": "20171003", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14032371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "US-BAUSCH-BL-2016-004530", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE C, SKOLNIK A, RASCHKE R, OWEN-REECE H, GRAEME K. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J.MED.TOXICOL.. 2016 FEB 08?.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160302", "receivedate": "20160302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12138143, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-HERITAGE PHARMACEUTICALS-2016HTG00246", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "206975", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50-90 TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016;12(3):301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161010", "receivedate": "20161010", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12834203, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "To describe the presentation and management of atypical subretinal lesions following initiation of antitubercular therapy for a tubercular choroidal granuloma.\nAn 18-year-old female was diagnosed with choroidal granuloma and shallow exudative retinal detachment in the left eye. Biopsy from a cervical lymph node was positive for tuberculosis. She was treated with antitubercular therapy (ATT) and oral steroids. After one week of therapy exudative detachment increased markedly and discrete yellowish-white subretinal lesions appeared first in the inferior periphery, then temporally and later involved the macula leading to a drop in visual acuity. A diagnosis of paradoxical worsening was considered and she was managed with a higher dose of oral corticosteroids, intravitreal methotrexate and intravitreal ranibizumab. The granuloma healed and the subretinal lesions as well as exudative detachment gradually resolved with improvement in visual acuity.\nSubretinal yellow-white lesions may develop as a paradoxical response to ATT.", "affiliations": "Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.", "authors": "Arora\|Atul\|A\|https://orcid.org/0000-0002-2192-8479;Katoch\|Deeksha\|D\|https://orcid.org/0000-0003-3646-5523;Jain\|Sahil\|S\|;Singh\|Simar Rajan\|SR\|https://orcid.org/0000-0003-0207-1913;Gupta\|Vishali\|V\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/09273948.2020.1780272", "fulltext": null, "fulltext_license": null, "issn_linking": "0927-3948", "issue": null, "journal": "Ocular immunology and inflammation", "keywords": "ATT; Ocular tuberculosis; SRHM; anti tubercular therapy; choroidal granuloma; paradoxical worsening; subretinal deposits", "medline_ta": "Ocul Immunol Inflamm", "mesh_terms": null, "nlm_unique_id": "9312169", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "32783681", "pubdate": "2020-08-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Yellow Subretinal Lesions following Initiation of Antituberculosis Therapy in A Tubercular Choroidal Granuloma: A Sign of Paradoxical Worsening?", "title_normalized": "yellow subretinal lesions following initiation of antituberculosis therapy in a tubercular choroidal granuloma a sign of paradoxical worsening" }	[ { "companynumb": "IN-LUPIN LIMITED-2022-08527", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090034", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, DURATION OF 9 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG, DURATION OF 9 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078939", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, DURATION OF 9 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DURATION OF 9 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "(0.05 ML OF 10 MG/ML)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "0.05", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "UNK, 400 MICROGRAM /0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Arora A, Katoch D, Jain S, Singh SR, Gupta V. Yellow Subretinal Lesions following Initiation of Antituberculosis Therapy in A Tubercular Choroidal Granuloma: A Sign of Paradoxical Worsening?. Ocular immunology and inflammation. 2022;30(1):29-33", "literaturereference_normalized": "yellow subretinal lesions following initiation of antituberculosis therapy in a tubercular choroidal granuloma a sign of paradoxical worsening", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20956167, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "IN-SA-2020SA225862", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBRETINAL HYPERREFLECTIVE EXUDATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "1000 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "031", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.05 ML OF 10 MG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "031", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.05 ML OF 10 MG/ML (SECOND DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBRETINAL HYPERREFLECTIVE EXUDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subretinal hyperreflective exudation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retinal detachment", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARORA A, KATOCH D, JAIN S, SINGH SR, GUPTA V. YELLOW SUBRETINAL LESIONS FOLLOWING INITIATION OF ANTITUBERCULOSIS THERAPY IN A TUBERCULAR CHOROIDAL GRANULOMA: A SIGN OF PARADOXICAL WORSENING. OCUL IMMUNOL INFLAMM.. 2020?UNK:UNK", "literaturereference_normalized": "yellow subretinal lesions following initiation of antituberculosis therapy in a tubercular choroidal granuloma a sign of paradoxical worsening", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200902", "receivedate": "20200902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18220843, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is known to be a rare and aggressive form of lymphoma that relapses quickly after both conventional chemotherapy and more targeted therapy. Lenalidomide is an immunomodulator that has shown safety and efficacy in multiple myeloma and is also approved for use in several types of lymphoma. In the case described here, the patient had a significant partial response to lenalidomide, which has not previously been described in this type of lymphoma. Given how aggressive and difficult to treat ALK+ LBCL is, further research is warranted to more completely elucidate the mechanism of action of lenalidomide in ALK+ LBCL and its role in treatment.", "affiliations": "Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.;Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA [email protected].", "authors": "Bhaskar\|Shakthi\|S\|;Abro\|Brooj\|B\|;Fraum\|Tyler J\|TJ\|;Mehta-Shah\|Neha\|N\|", "chemical_list": "D007155:Immunologic Factors; D000077548:Anaplastic Lymphoma Kinase; D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-235578", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(8)", "journal": "BMJ case reports", "keywords": "cancer intervention; therapeutic indications", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D000077269:Lenalidomide; D017728:Lymphoma, Large-Cell, Anaplastic; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32843459", "pubdate": "2020-08-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase-positive large B-cell lymphoma.", "title_normalized": "lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase positive large b cell lymphoma" }	[ { "companynumb": "US-CELGENEUS-USA-20200900325", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": "15 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": "20 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" } ], "patientagegroup": null, "patientonsetage": "84", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spinal fracture", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Performance status decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dementia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHASKAR S. LENALIDOMIDE DEMONSTRATES CLINICAL ACTIVITY IN ANAPLASTIC LYMPHOMA KINASE?POSITIVE LARGE B?CELL LYMPHOMA. BMJ CASE REPORTS. 2020 AUG 25?.", "literaturereference_normalized": "lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase positive large b cell lymphoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200909", "receivedate": "20200909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18245746, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Platinum-based chemotherapeutic agents are commonly used in the treatment of several cancers. While effective, they are often discontinued due to toxicities and hypersensitivity reactions (HSRs) that occur more frequently with repeated exposure. Following discontinuation of one agent, therapy may be continued with a second platinum salt, though the cross-reactivity between agents in this class is not well understood. This is particularly true for alternative routes of administration such as hyperthermic intraperitoneal chemotherapy (HIPEC). In this case report, we describe the use of cisplatin during HIPEC in a patient who previously experienced an HSR to systemic oxaliplatin. The patient tolerated HIPEC including 200 mg cisplatin for 1 hour without any adverse effects and did not require a desensitization protocol prior to therapy. This case suggests that HIPEC with platinum-based agents can be performed in patients with prior HSRs to systemic therapy, though further studies are needed to understand safety parameters, the cross-reactivity between agents and the necessity of skin testing or desensitization protocols.", "affiliations": "Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.;Department of Pharmacy, University of Chicago Medical Center, Chicago, IL, USA.;Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.;Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.", "authors": "Morgan\|Ryan\|R\|https://orcid.org/0000-0002-4201-166X;Parsad\|Sandeep\|S\|https://orcid.org/0000-0002-7256-7212;Turaga\|Kiran K\|KK\|https://orcid.org/0000-0001-8541-586X;Eng\|Oliver S\|OS\|https://orcid.org/0000-0003-0226-5005", "chemical_list": "D000077150:Oxaliplatin; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1111/bcpt.13464", "fulltext": null, "fulltext_license": null, "issn_linking": "1742-7835", "issue": "127(6)", "journal": "Basic & clinical pharmacology & toxicology", "keywords": "HIPEC; cisplatin; hypersensitivity; oxaliplatin; platinum salt", "medline_ta": "Basic Clin Pharmacol Toxicol", "mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018450:Disease Progression; D004342:Drug Hypersensitivity; D006801:Humans; D000084262:Hyperthermic Intraperitoneal Chemotherapy; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D013274:Stomach Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "101208422", "other_id": null, "pages": "551-553", "pmc": null, "pmid": "32623784", "pubdate": "2020-12", "publication_types": "D002363:Case Reports", "references": null, "title": "HIPEC with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin.", "title_normalized": "hipec with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin" }	[ { "companynumb": "US-FRESENIUS KABI-FK202008365", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "077776", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN (MANUFACTURER UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLINIC ACID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL SODIUM" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORGAN R, PARSAD S, TURAGA K, ENG O. HIPEC WITH CISPLATIN IN A PATIENT WITH A PRIOR HYPERSENSITIVITY REACTION TO SYSTEMIC OXALIPLATIN. 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HIPEC WITH CISPLATIN IN A PATIENT WITH A PRIOR HYPERSENSITIVITY REACTION TO SYSTEMIC OXALIPLATIN. BASIC + CLINICAL PHARMACOLOGY + TOXICOLOGY. 2020 JUL 05?. 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chest discomfort", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lip swelling", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORGAN R, PARSAD S, TURAGA KK, ENG OS. HIPEC WITH CISPLATIN IN A PATIENT WITH A PRIOR HYPERSENSITIVITY REACTION TO SYSTEMIC OXALIPLATIN. BASIC?CLIN?PHARMACOL?TOXICOL 2020?:NO PAGINATION.", "literaturereference_normalized": "hipec with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200831", "receivedate": "20200826", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18198949, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-CIPLA LTD.-2020US05570", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired quality of life", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORGAN R, PARSAD S, TURAGA KK, ENG OS.. HIPEC WITH CISPLATIN IN A PATIENT WITH A PRIOR HYPERSENSITIVITY REACTION TO SYSTEMIC OXALIPLATIN. BASIC AND CLINICAL PHARMACOLOGY AND TOXICOLOGY. 2020?00:1 TO 3", "literaturereference_normalized": "hipec with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200814", "receivedate": "20200814", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18147943, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "BACKGROUND Serotonin syndrome is a common yet potentially life-threatening condition caused by increased serotonergic activity, usually from serotonergic pharmaceutical agents. Primary features of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. However, the presentation of serotonin syndrome is often quite variable, leading to its under-diagnosis. CASE REPORT A 50-year-old female with chronic kidney disease on peritoneal dialysis presented to the Emergency Department with severe, diffuse body pain. Over the course of her hospital stay, she developed severe nausea, vomiting, and diarrhea followed by hyperreflexia and inducible clonus. Laboratory studies were remarkable for elevated liver transaminases. Review of her medications revealed several serotonergic agents, including duloxetine, tramadol, and ondansetron. Given her symptoms and the multiple serotonergic agents she was taking, she was diagnosed with serotonin syndrome. Discontinuation of the serotonergic agents led to resolution of her symptoms over the course of 4 days. CONCLUSIONS Our patient's initial presentation of diffuse body pain highlights the variable presentation of serotonin syndrome. Our case also demonstrates the importance of recognizing serotonin syndrome, as the supportive ondansetron we gave to alleviate her nausea and vomiting likely exacerbated her serotonin syndrome.", "affiliations": "University of Florida College of Medicine, Gainesville, FL, USA.;University of Florida College of Medicine, Gainesville, FL, USA.;Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Medicine, University of Florida, Gainesville, FL, USA.", "authors": "Guo\|Michael H\|MH\|;Monir\|Reesa L\|RL\|;Wright\|Ashleigh\|A\|;Holland\|Neal P\|NP\|", "chemical_list": "D017367:Serotonin Uptake Inhibitors", "country": "United States", "delete": false, "doi": "10.12659/AJCR.911204", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3031850410.12659/AJCR.911204911204ArticlesCase of Serotonin Syndrome Initially Presenting as Diffuse Body Pain Guo Michael H. ABCDEFG1Monir Reesa L. ABCDEF1Wright Ashleigh ACDE2Holland Neal P. ABCDEFG2\n1 University of Florida College of Medicine, Gainesville, FL, U.S.A.\n2 Department of Medicine, University of Florida, Gainesville, FL, U.S.AAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Neal P. Holland, e-mail: [email protected] 15 10 2018 19 1227 1231 17 5 2018 12 7 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 50\n\nFinal Diagnosis: Serotonin syndrome\n\nSymptoms: Pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: General and Internal Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nSerotonin syndrome is a common yet potentially life-threatening condition caused by increased serotonergic activity, usually from serotonergic pharmaceutical agents. Primary features of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. However, the presentation of serotonin syndrome is often quite variable, leading to its under-diagnosis.\n\nCase Report:\nA 50-year-old female with chronic kidney disease on peritoneal dialysis presented to the Emergency Department with severe, diffuse body pain. Over the course of her hospital stay, she developed severe nausea, vomiting, and diarrhea followed by hyperreflexia and inducible clonus. Laboratory studies were remarkable for elevated liver transaminases. Review of her medications revealed several serotonergic agents, including duloxetine, tramadol, and ondansetron. Given her symptoms and the multiple serotonergic agents she was taking, she was diagnosed with serotonin syndrome. Discontinuation of the serotonergic agents led to resolution of her symptoms over the course of 4 days.\n\nConclusions:\nOur patient’s initial presentation of diffuse body pain highlights the variable presentation of serotonin syndrome. Our case also demonstrates the importance of recognizing serotonin syndrome, as the supportive ondansetron we gave to alleviate her nausea and vomiting likely exacerbated her serotonin syndrome.\n\nMeSH Keywords:\nAbnormalities, Drug-InducedAntidepressive AgentsSerotonin Syndrome\n==== Body\nBackground\nSerotonin syndrome, or serotonin toxicity, is a constellation of symptoms that result from increased serotonergic activity. The syndrome is usually caused by increased serotonin levels as a result of medications that have serotonergic activity. Although serotonin syndrome is classically caused by selective serotonin reuptake inhibitors (SSRIs), other pharmaceutical agents have also been implicated. These including antipsychotics, narcotics, dietary supplements, anti-epileptics, and antibiotics, among many others [1]. The syndrome is quite common, although reliable estimates of its prevalence have been hampered by challenges with recognition of the syndrome owing to its variable presentation. However, a post-marketing surveillance study of the SSRI nefazodone identified an incidence of 0.4 cases per 1000 patient-months [2]. In addition, a study revealed that 14–16% of cases of overdose of SSRIs develop symptoms of serotonin syndrome [3].\n\nSerotonin syndrome is the result of increased serotonin in the central nervous system (CNS) and peripheral nervous system [3]. It is believed that the serotonin receptor 5-HT2A is primarily responsible for these effects, although other neurotransmitter receptors have also been implicated [4,5]. In the CNS, serotonin is normally produced from the median raphe nucleus and has a wide range of effects on behavior, mood appetite, autonomic function, thermoregulation, and nociception, amongst others. In the periphery, serotonin acts to modulate gastrointestinal motility and vascular tone. The clinical manifestations of serotonin syndrome are a reflection of the effects of excessive serotonin on these physiologic systems.\n\nThe classic clinical triad of serotonin syndrome is comprised of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities (Table 1). However, the clinical presentation of serotonin syndrome is quite variable and non-specific [6], often making the diagnosis quite challenging. Furthermore, no single laboratory test, including serum serotonin levels, can reliably confirm the diagnosis, and there are no pathognomonic clinical findings [7]. Currently, the Hunter Criteria is the best diagnostic criteria (Table 1), and has a reported sensitivity of 84% and specificity of 97% [7]. Timely diagnosis is imperative, as serotonin syndrome can be life-threatening given the autonomic instability. Life-threatening and related complications of the condition include severe hypertension and tachycardia that lead to shock, hyperthermia, rhabdomyolysis, renal failure, and disseminated intravascular coagulation, among others [1]. The cornerstone of treatment is discontinuation of all serotonergic agents and supportive measures [1], as well as possible administration of anti-serotonergic agents such as cyproheptadine in more severe cases [8].\n\nCase Report\nA 50-year-old female with medical history notable for stage 5 chronic kidney disease on nightly home peritoneal dialysis, type II diabetes mellitus, peripheral neuropathy, gastroesophageal reflux disease, hypertension, and unspecified chronic pain presented to the Emergency Department (ED) with a 1-day history of worsened nausea and severe diffuse body pain, most notably of her abdomen. Her pain began the evening prior to admission during a home peritoneal dialysis treatment, which she stopped promptly due to the development of her severe pain.\n\nOn review of her history, she had experienced similar symptoms approximately 1 month ago, also during a home perito-neal dialysis session. With the prior episode, the pain subsided when she stopped her dialysis session. It was later determined by her nephrologist that this pain was caused by gas introduced during dialysis.\n\nOn initial physical examination, she appeared anxious and acutely in distress from her pain. Vital signs revealed that she was afebrile and with blood pressure of 148/82 mmHg, heart rate of 109 beats per minute and respiratory rate of 18 breaths per minute. She complained of pain on light palpation to any portion of her body, including her entire abdomen. Her cardiac and pulmonary examinations were unremarkable. Her liver span and spleen size could not be determined as the patient was unable to tolerate examination. No ascites or edema was noted. She was able to move all extremities spontaneously, and no focal neurological deficits were observed. She did display bilateral asterixis. Her deep tendon reflexes were normal on initial exam, and her tone was judged to be normal.\n\nIn the ED, initial laboratory investigations revealed elevated blood urea nitrogen (BUN) and creatinine levels, consistent with her chronic kidney disease and not changed significantly from baseline (Table 2). She had a normocytic, normochromic anemia, which was unchanged from her baseline, but her white blood cell count and differential was within normal limits. Liver enzymes were notable for increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase, but her bilirubin was within normal limits.\n\nHepatitis A, B, and C serologies were all negative. Serum lipase was not elevated. Peritoneal fluid analysis was also performed. Peritoneal fluid was cloudy and showed elevated white blood cells (WBCs) (4% neutrophils), but the gram stain of her peritoneal fluid did not show any organisms (Table 3).\n\nComputed tomography with IV contrast of the abdomen was performed. It was remarkable for wedge-shaped areas of hypodensity in the spleen that were read as possibly representing infarction. A right upper quadrant ultrasound was unremarkable, with no abnormal findings in the liver, gallbladder, pancreas, or biliary tree.\n\nShe was admitted to the hospital with concern that her pain was again related to her peritoneal dialysis catheter or her dialysis treatment. Over the first 3 days of her hospitalization, her pain worsened. In addition, she developed worsening nausea, severe retching, non-bloody diarrhea, and recurrent non-bloody, non-bilious vomiting. She was given ondansetron for symptomatic treatment of her nausea without relief. She was switched to promethazine, but her symptoms continued to worsen. She also had episodic hypertension, with systolic blood pressure as high as 234 mmHg. She continued to display asterixis, and on day 3 of hospitalization, she was found to have inducible clonus and new patellar hyperreflexia bilaterally.\n\nGiven the negative workup, her medication history was reviewed carefully in search for an underlying cause for her symptoms. On further review, it was noted that she had been taking multiple pharmaceutical agents with serotonergic properties. She was prescribed duloxetine (30 mg oral twice a day) for her peripheral neuropathy and had been using tramadol (50 mg oral) on an as needed basis for pain as well. She also was taking promethazine (12.5–25 mg oral) at home as needed for mild nausea. During her hospital stay, she was given a total of 16 mg in doses of 4 mg of ondansetron for symptomatic treatment of her nausea and vomiting, which was switched to promethazine when ondansetron was ineffective and received one 25 mg dose of intravenous promethazine. Duloxetine, tramadol, and ondansetron all have serotonergic properties and have been known to cause or contribute to serotonin syndrome [1]. Given her overall presentation and when considering her mediation use, she was diagnosed with serotonin syndrome.\n\nFollowing our diagnosis of serotonin syndrome, we discontinued all of her serotonergic medications, including duloxetine, tramadol, and ondansetron. We also discontinued her promethazine, as promethazine is associated with neuroleptic malignant syndrome, an important differential diagnosis whose features can mimic serotonin syndrome (see Discussion). As she did not exhibit life-threatening autonomic instability, more aggressive measures such as cyproheptadine were not warranted in her case. She was closely observed, with daily laboratory investigations and close tracking of her vital signs. She started to improve symptomatically within 1 day of discontinuation of her serotonergic agents. By day 3 (hospital day 6) following discontinuation of her serotonergic agents, her diffuse pain, clonus, and tremor had resolved. Her liver enzymes also trended down and were nearly completely normalized by day 6 of hospitalization.\n\nWith resolution of her symptoms, she was discharged after discontinuation of her serotonergic agents. She was instructed to follow up with her primary care provider to consider restarting her duloxetine for her underlying chronic pain under close monitoring.\n\nDiscussion\nThis patient initially presented with a variety of symptoms that did not fit a single unifying diagnosis. Her initial presenting symptoms of severe, diffuse, non-anatomical pain that was seemingly temporally related to her peritoneal dialysis caused us to consider primarily gastrointestinal and somatoform etiologies. However, when she developed clonus and hyperreflexia as well as numerous autonomic symptoms (nausea, vomiting, diarrhea, and episodic hypertension) during her hospital stay, we were able to recognize her constellation of symptoms as serotonin syndrome.\n\nCareful medication review did reveal several serotonergic agents the patient was taking prior to admission – duloxetine and tramadol. Furthermore, as her symptoms progressed and worsened during her stay, she was given ondansetron and promethazine at increasing dosages for symptomatic relief. Ondansetron inhibits the serotonin receptor 5-HT3, and for unclear reasons, has been associated with serotonin syndrome [9,10]. The combination of these medications allowed more classic symptoms and exam findings of serotonin syndrome (e.g., clonus and hyperreflexia) to manifest and allowed us to make the diagnosis. Our diagnosis was corroborated by the rapid resolution of symptoms following discontinuation of the serotonergic agents over the course of 4 days.\n\nA confounding aspect of this case is the temporal relationship of her symptoms to her peritoneal dialysis. In the present incident, as well as in the incident 1 month prior, she experienced severe diffuse pain following peritoneal dialysis. In the incident 1 month prior, her nephrologist had determined that gas had entered the peritoneum to trigger the pain episode. However, during this episode, no malfunction of the peritoneal dialysis catheter or the dialysis process itself could be identified. We believe that in both episodes, a possible malfunction related to her peritoneal dialysis occurred, but at this point, we do not believe that the peritoneal dialysis itself was the direct instigator of her serotonin syndrome.\n\nA diagnostic consideration in this case was neuroleptic malignant syndrome (NMS). NMS is associated with use of anti-psychotics, including promethazine, which the patient was taking prior to admission and which was additionally given to her for nausea while in the hospital [11]. NMS is classically associated with fever, muscular rigidity, and autonomic dysfunction, thus sharing many features with serotonin syndrome. However, there were several reasons why we favored serotonin syndrome over NMS. First, the patient was afebrile on admission. Second, the patient did not display frank muscle rigidity that is classic for NMS. Lastly, NMS is usually associated with abrupt escalations in the causal agent, and there was no indication that this was the case prior to her admission. Nonetheless, NMS is an important differential diagnosis in cases of serotonin syndrome. Another diagnostic consideration in this case was malignant hyperthermia, which is characterized by fever, muscular rigidity, and tachycardia [12].\n\nHowever, malignant hyperthermia is usually associated with use of depolarizing anesthetic agents (which the patient was not taking), and the patient was afebrile.\n\nIn addition, the patient had moderately elevated liver transaminases on admission (Table 2). They were noted to be down trending on follow-up labs on hospital day 2 and continued to downtrend to near normal levels after we discontinued her serotonergic agents. Prior reports have also indicated that increased liver transaminases can be seen in serotonin syndrome [1,13]. Our report provides additional evidence of elevated liver transaminases as a possible feature of serotonin syndrome.\n\nThe patient’s presenting symptom of diffuse pain is not typically associated with serotonin syndrome. However, a recent 12 patient case series identified generalized pain in 4 patients (33%) with serotonin syndrome [14]. Moreover, clonus, which is often considered as a cardinal symptom of serotonin syndrome, was only seen in 5 of the 12 patients in that study (42%). These results highlight the significant variability of serotonin syndrome and the importance for clinicians to be vigilant for this diagnosis.\n\nAn important point in this case is our initial use of ondansetron – a drug with serotonin-modifying properties – for symptomatic treatment of the patient’s nausea. Our liberal use of these medications very likely exacerbated her serotonin syndrome, worsening her nausea, vomiting, and diarrhea and allowing the clonus and hyperreflexia to manifest. Thus, it is important to recognize serotonin syndrome early, as symptomatic treatment of its symptoms may involve use of medications that will greatly worsen the condition.\n\nConclusions\nDiffuse body pain may be an initial presentation of serotonin syndrome. Medications such as ondansetron used to symptomatically treat the nausea and vomiting that may accompany serotonin syndrome can actually exacerbate the condition.\n\nTable 1. Symptoms associated with serotonin syndrome.\n\nHunter criteria symptoms of serotonin syndrome\t\n• Clonus\t\n – Spontaneous\t\n – Inducible\t\n – Ocular\t\n• Tremor\t\n• Hyperreflexia\t\n• Hypertonia\t\n• Hyperthermia\t\nOther manifestations\t\n• Altered mental status\t\n• Autonomic instability\t\n – Tachycardia\t\n – Hyperthermia\t\n – Hypertension\t\n – Vomiting\t\n• Diarrhea\t\n• Mydriasis\t\n• Diaphoresis\t\n• Pain\t\n• Flushing\t\n• Trismus\t\nTable 2. Selected laboratory measurements on admission.\n\nLab\tValue\tReference range\t\nWhite blood cell count\t7.7\t4.0–10.0 103/mL\t\nHemoglobin\t9.8\t12.0–16.0 g/dL\t\nHematocrit\t29.7\t35.9–45.0%\t\nMean corpuscular volume\t94.2\t78.0–100.0 fL\t\nPlatelet Count\t230\t150–400 103/mL\t\nAspartate aminotransferase (AST)\t572\t0–37 IU/L\t\nAlanine aminotransferase (ALT)\t391\t0–41 IU/L\t\nDirect Bilirubin\t<0.2\t0.0–0.2 mg/dL\t\nTotal Bilirubin\t0.3\t0.0–1.0 mg/dL\t\nAlkaline phosphatase\t433\t35–129 IU/L\t\nBlood urea nitrogen\t75\t6–20 mg/dL\t\nCreatinine\t10.42\t0.40–0.9 mg/dL\t\nTable 3. Peritoneal fluid analysis.\n\nLab\tValue\tReference range\t\nAppearance\tCloudy\tNA\t\nWhite blood cell count\t1410\t<5/mL\t\n Eosinophil %\t4\t0–0%\t\n Polymorphonuclear %\t4\t0–0%\t\n Monocyte/macrocyte %\t61\t0–0%\t\n Lymphocyte %\t31\t0–0%\t\nRed blood cell count\t570\t0/mL\n==== Refs\nReferences:\n1. Boyer EW Shannon M The serotonin syndrome N Engl J Med 2005 352 1112 20 15784664 \n2. Mackay FJ Dunn NR Mann RD Antidepressants and the serotonin syndrome in general practice Br J Gen Pract 1999 49 871 74 10818650 \n3. Isbister GK Bowe SJ Dawson A Whyte IM Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose J Toxicol Clin Toxicol 2004 42 277 85 15362595 \n4. Nisijima K Shioda K Yoshino T Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome Neurochem Int 2003 43 155 64 12620284 \n5. Nisijima K Yoshino T Yui K Katoh S Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome Brain Res 2001 890 23 31 11164765 \n6. Frank C Recognition and treatment of serotonin syndrome Can Fam Physician 2008 54 988 92 18625822 \n7. Dunkley EJC Isbister GK Sibbritt D The hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity QJM 2003 96 635 42 12925718 \n8. Lappin RI Auchincloss EL Treatment of the serotonin syndrome with cyproheptadine N Engl J Med 1994 331 1021 22 \n9. Turkel SB Nadala JGB Wincor MZ Possible serotonin syndrome in association with 5-HT3 antagonist agents Psychosomatics 2001 42 258 60 11351116 \n10. Gollapudy S Kumar V Dhamee MS A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion J Clin Anesth 2012 24 251 52 22537574 \n11. Berman BD Neuroleptic malignant syndrome: A review for neurohospitalists Neurohospitalist 2011 1 41 47 23983836 \n12. Glahn KPE Ellis FR Halsall PJ Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group Br J Anaesth 2010 105 417 20 20837722 \n13. Malik A Junglee N A case of the serotonin syndrome secondary to phenelzine monotherapy at therapeutic dosing Case Rep Med 2015 2015 931963 25861278 \n14. Prakash S Patel V Kakked S Mild serotonin syndrome: A report of 12 cases Ann Indian Acad Neurol 2015 18 226 30 26019424\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "19()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D059350:Chronic Pain; D005260:Female; D006801:Humans; D008875:Middle Aged; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors", "nlm_unique_id": "101489566", "other_id": null, "pages": "1227-1231", "pmc": null, "pmid": "30318504", "pubdate": "2018-10-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11164765;12925718;12620284;25861278;15362595;22537574;8084345;20837722;11351116;10818650;26019424;15784664;18625822;23983836", "title": "Case of Serotonin Syndrome Initially Presenting as Diffuse Body Pain.", "title_normalized": "case of serotonin syndrome initially presenting as diffuse body pain" }	[ { "companynumb": 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CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN.. THE AMERICAN JOURNAL OF CASE REPORTS. 2018?19:1227-1231. DOI:10.12659/AJCR.911204", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190506", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792767, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-ZYDUS-036677", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090404", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL OF 16MG IN DOSES OF 4MG OF ONDANSETRON", "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "040596", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5-25 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090728", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE/DULOXETINE HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL OF 16MG IN DOSES OF 4MG OF ONDANSETRON", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "040596", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "040596", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Normochromic normocytic anaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retching", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asterixis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO MH, MONIR RL, WRIGHT A, HOLLAND NP. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. AM-J-CASE-REP 2018?191227-1231.", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190511", "receivedate": "20190511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16301468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-QILU PHARMACEUTICAL CO.LTD.-QLU-000784-2018", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, PRN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203711", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL OF 16 MG, IN DOSES OF 4 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5-25 MG, AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retching", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asterixis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO MH MONIR RL WRIGHT A HOLLAND NP. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. AM J CASE REP.. 2018?19:1227-1231", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181105", "receivedate": "20181105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15585742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2019-US-1049602", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "76759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED A TOTAL OF 16MG IN DOSES OF 4MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "75982", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090776", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "76759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "40454", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HOME MEDICATION (PRIOR TO HOSPITALISATION): 12.5-25MG AS REQUIRED FOR NAUSEA", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "40454", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED A SINGLE DOSE DURING HOSPITALISATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GUO MH, MONIR RL, WRIGHT A, HOLLAND NP. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. AM-J-CASE-REP 2018?19:1227-1231.", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190515", "receivedate": "20190515", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16314772, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "US-PFIZER INC-2018449309", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "25 MG, SINGLE (DURING HER HOSPITAL STAY, SHE RECEIVED ONE 25 MG DOSE OF INTRAVENOUS PROMETHAZINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE HCL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "077473", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "16", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": "16 MG (TOTAL OF 16 MG IN DOSES OF 4 MG OF ONDANSETRON)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "077473", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "16", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5?25 MG ORAL AT HOME AS NEEDED FOR MILD NAUSEA", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO, M.. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. THE AMERICAN JOURNAL OF CASE REPORTS. 2018?19:1227?1231", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210728", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15598060, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-18-08121", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "083312", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING HER HOSPITAL STAY, SHE RECEIVED ONE 25 MG DOSE OF INTRAVENOUS PROMETHAZINE ; IN TOTAL", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "083312", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "083312", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5?25 MG ORAL AT HOME AS NEEDED FOR MILD NAUSEA ; AS NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076780", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": "16", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076780", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": "16", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO M,MONIR R,WRIGHT A,HOLLAND N. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. THE AMERICAN JOURNAL OF CASE REPORTS 2018?19:1227-1231.", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181107", "receivedate": "20181107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15595920, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "OBJECTIVE\nTo describe a paradigm of care for patients with ocular inflammatory diseases aimed at induction of durable remission.\n\n\nMETHODS\nRetrospective cohort study. The records of 399 patients with ocular inflammatory diseases treated with systemic immunomodulatory therapy (IMT) at the Massachusetts Eye Research and Surgery Institution were reviewed. Durable remission was defined as control of inflammation in the absence of systemic IMT for at least 1 year. Fifty patients met the inclusion criteria.\n\n\nRESULTS\nMean age was 46+/-22.5 years (range 18-88). All the patients had corticosteroid therapy and failed this therapy before having IMT. Fifty-two percent of the patients had used methotrexate alone or in combination with other medications. Thirty percent of the patients required at least 2 years of therapy with systemic IMT to obtain durable remission, while 44% required 2 to 5 years of therapy to achieve the same. Twenty percent continued to stay in remission, off immunomodulatory drugs, between 2 and 5 years and 18% were in remission for more than 5 years after therapy discontinuation.\n\n\nCONCLUSIONS\nIMT can be sight saving in patients. It can be tapered and discontinued successfully without the return of ocular inflammation. Durable drug-free remission is an achievable goal, and should be pursued by ocular inflammatory disease specialists.", "affiliations": "Massachusetts Eye Research and Surgery Institution, Cambridge, MA 02142, USA.", "authors": "Cervantes-Castaneda\|R A\|RA\|;Bhat\|P\|P\|;Fortuna\|E\|E\|;Acevedo\|S\|S\|;Foster\|C S\|CS\|", "chemical_list": "D007155:Immunologic Factors; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1177/112067210901900117", "fulltext": null, "fulltext_license": null, "issn_linking": "1120-6721", "issue": "19(1)", "journal": "European journal of ophthalmology", "keywords": null, "medline_ta": "Eur J Ophthalmol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017211:Treatment Failure; D014605:Uveitis; D055815:Young Adult", "nlm_unique_id": "9110772", "other_id": null, "pages": "118-23", "pmc": null, "pmid": "19123158", "pubdate": "2009", "publication_types": "D016428:Journal Article", "references": null, "title": "Induction of durable remission in ocular inflammatory diseases.", "title_normalized": "induction of durable remission in ocular inflammatory diseases" }	[ { "companynumb": "US-APOTEX-2021AP032191", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunomodulatory therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypercholesterolaemia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cervantes-Castaneda RA, Bhat P, Fortuna E, Acevedo S, Foster CS.. Induction of durable remission in ocular inflammatory diseases.. European Journal of Ophthalmology. 2009;19(1):118-123", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220603", "receivedate": "20220603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20909917, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220720" }, { "companynumb": "NVSC2021US179853", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EYE INFLAMMATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EYE INFLAMMATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CERVANTES?CASTANEDA RA, BHAT P, FORTUNA E, ACEVEDO S, FOSTER S. INDUCTION OF DURABLE REMISSION IN OCULAR INFLAMMATORY DISEASES. EUROPEAN JOURNAL OF OPHTHALMOLOGY. 2009?19(1):118?23", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210811", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19687367, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-APOTEX-2021AP032195", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunomodulatory therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cervantes-Castaneda RA, Bhat P, Fortuna E, Acevedo S, Foster CS.. Induction of durable remission in ocular inflammatory diseases.. European Journal of Ophthalmology. 2009;19 (1):118-123", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220603", "receivedate": "20220603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20910016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" }, { "companynumb": "US-APOTEX-2021AP032190", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunomodulatory therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypercholesterolaemia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cervantes-Castaneda RA, Bhat P, Fortuna E, Acevedo S, Foster CS.. Induction of durable remission in ocular inflammatory diseases.. European Journal of Ophthalmology. 2009;19(1):118-123", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220603", "receivedate": "20220603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20909580, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "BACKGROUND\nConcerns about the side effects and interactions of biologic drugs with reproduction and pregnancy have been always an issue between experts. The safety of these therapies during conception and/or pregnancy is not fully understood. The aim of this study was to assess the exposure to biologic drugs before and/or during conception/pregnancy and the risk of adverse pregnancy outcomes in women with rheumatic diseases.\n\n\nMETHODS\nWe conducted a cohort study of pregnancies reported in women with immune-mediated rheumatic diseases registered at the Rheumatic Diseases Portuguese Registry (Reuma.pt) and exposed to biologic drugs. Data concerning fetal and maternal outcomes (live birth, spontaneous abortion, neonatal and intrauterine death, intrauterine growth restriction, premature delivery, congenital malformations, neonatal lupus, voluntary or medical interruption of pregnancy, disease flares and need for treatment with other drugs) was extracted.\n\n\nRESULTS\nIn total, 69 pregnancies from 56 females were analysed, the majority with the diagnosis of spondyloarthritis or rheumatoid arthritis. In almost half of the cases (n=32, 46.4%) the biologic was stopped for pregnancy planning, in 31 cases (44.9%) it was stopped when pregnancy was diagnosed and in 6 pregnancies (8.7%) biologic therapy was maintained, at least until the 2nd trimester. There were 76.8% of live births and 22% of spontaneous abortions. Congenital anomalies were reported in 2 newborns.\n\n\nCONCLUSIONS\nIn half cases, it was decided to stop biologic therapy in the family planning period. Using biologic disease-modifying anti-rheumatic drugs before and/or during pregnancy doesn't seem to affect the overall maternal and fetal outcomes. Pregnancy planning and treatment options should be discussed and a shared decision should be established between physician and patient.", "affiliations": "Centro Hospitalar e Universitário de Coimbra.;Instituto Português de Reumatologia.;Unidade Local de Saúde do Alto Minho.;Centro Hospitalar Lisboa Ocidental.;Centro Hospitalar Tondela Viseu.;Centro Hospitalar Baixo Vouga.;Hospital Garcia da Orta.;Hospital Central do Funchal.;Centro Hospitalar e Universitário Lisboa Norte.;Centro Hospitalar Algarve.;Centro Hospitalar S.João.;Centro Hospitalar e Universitário de Coimbra.;Centro Hospitalar e Universitário de Coimbra.;Hospital Garcia da Orta.", "authors": "Brites\|Luisa\|L\|;Madeira\|Nathalie\|N\|;Rodrigues\|Joana\|J\|;Marona\|José\|J\|;Martins\|Nádia\|N\|;Águeda\|Ana\|A\|;Freitas\|Raquel\|R\|;Neto\|Agna\|A\|;Capela\|Susana\|S\|;Sequeira\|Graça\|G\|;Ganhão\|Sara\|S\|;Duarte\|Cátia\|C\|;Santiago\|Mariana\|M\|;Santos\|Maria José\|MJ\|", "chemical_list": "D018501:Antirheumatic Agents", "country": "Portugal", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0303-464X", "issue": "44(4)", "journal": "Acta reumatologica portuguesa", "keywords": null, "medline_ta": "Acta Reumatol Port", "mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001691:Biological Therapy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D016742:Preconception Care; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011295:Prenatal Care; D012189:Retrospective Studies; D012216:Rheumatic Diseases", "nlm_unique_id": "0431702", "other_id": null, "pages": "266-272", "pmc": null, "pmid": "32008032", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": null, "title": "Biologic therapy use and pregnancy outcomes in women with immune-mediated inflammatory rheumatic diseases.", "title_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases" }	[ { "companynumb": "PT-MYLANLABS-2020M1098899", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "761154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal growth restriction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRITES L, MADEIRA N, RODRIGUES J, MARONA J, MARTINS N, AGUEDA A, ET AL. BIOLOGIC THERAPY USE AND PREGNANCY OUTCOMES IN WOMEN WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES. ACTA-REUMATOL-PORT 2019?44(4):266-272.", "literaturereference_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571628, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "PT-MYLANLABS-2020M1098884", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": "1", "drugadministrationroute": "064", "drugauthorizationnumb": "761154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cleft palate", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRITES L, MADEIRA N, RODRIGUES J, MARONA J, MARTINS N, AGUEDA A, ET AL. BIOLOGIC THERAPY USE AND PREGNANCY OUTCOMES IN WOMEN WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES. ACTA-REUMATOL-PORT 2019?44(4):266-272.", "literaturereference_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "PT-MYLANLABS-2020M1098901", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": "1", "drugadministrationroute": "064", "drugauthorizationnumb": "761154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypospadias", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRITES L, MADEIRA N, RODRIGUES J, MARONA J, MARTINS N, AGUEDA A, ET AL. BIOLOGIC THERAPY USE AND PREGNANCY OUTCOMES IN WOMEN WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES. ACTA-REUMATOL-PORT 2019?44(4):266-272.", "literaturereference_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]
{ "abstract": "BACKGROUND\nLacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration.\n\n\nRESULTS\nA 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship.\n\n\nCONCLUSIONS\nThis case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.", "affiliations": null, "authors": "Sunwoo\|Jun-Sang\|JS\|;Byun\|Jung-Ick\|JI\|;Lee\|Sang Kun\|SK\|", "chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D015415:Biomarkers; D000078334:Lacosamide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase", "country": "Germany", "delete": false, "doi": "10.5414/CP202282", "fulltext": null, "fulltext_license": null, "issn_linking": "0946-1965", "issue": "53(6)", "journal": "International journal of clinical pharmacology and therapeutics", "keywords": null, "medline_ta": "Int J Clin Pharmacol Ther", "mesh_terms": "D000081:Acetamides; D000410:Alanine Transaminase; D000927:Anticonvulsants; D001219:Aspartate Aminotransferases; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D004796:Clinical Enzyme Tests; D004833:Epilepsy, Temporal Lobe; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008111:Liver Function Tests; D011237:Predictive Value of Tests; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "9423309", "other_id": null, "pages": "471-3", "pmc": null, "pmid": "25907173", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of lacosamide-induced hepatotoxicity.", "title_normalized": "a case of lacosamide induced hepatotoxicity" }	[ { "companynumb": "KR-UCBSA-2015015059", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022253", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TIANEPTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TIANEPTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SUNWOO JS, BYUN JI, LEE SK. A CASE OF LACOSAMIDE-INDUCED HEPATOTOXICITY. INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS. 2015", "literaturereference_normalized": "a case of lacosamide induced hepatotoxicity", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20150514", "receivedate": "20150514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11111559, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "Objectives: To report an oxcarbazepine (OXC)-induced cutaneous reaction in a female of Mexican ancestry. Case Summary: A 60-year-old female of Mexican ancestry presented to clinic with a diffuse morbilliform rash, with erythema and eruptions of papules/pustules concentrated on her neck and torso. The rash appeared 1 week following the initiation of OXC for trigeminal neuralgia. Initially, the correlation between the reaction and initiation of OXC was not recognized by the provider. OXC was continued for a total of 4 weeks and several medical encounters transpired in the interim. Supportive therapy, in the form of oral antihistamines and oral/topical corticosteroids, failed to resolve the rash. A clinical pharmacist prompted the discontinuation of OXC due to suspicion that it incited the adverse reaction. Oral corticosteroid therapy was initiated and tapered over 2 weeks, with rash dissipation occurring in 1 month. Discussion: The association of OXC with the cutaneous eruption was classified as \"probable\" based on the Naranjo Scale. While financial resources were not available to perform genetic testing, it may be possible that the genetic status of this patient lent itself to greater potential for cutaneous reactions with OXC. Further research is needed to determine whether pharmacogenetic variables affiliated with pre-Columbian lineage may predispose individuals to specific adverse drug reactions. Conclusion: As regional genotypes disperse globally, it is imperative that clinicians are cognizant of risks regarding genetically implicated adverse drug reactions. While information is limited for certain ethnicities, it is essential that providers diligently monitor all populations for reactions characteristic to specific medications.", "affiliations": "University of Texas at Tyler, Tyler, TX, USA.;University of Texas at Tyler, Tyler, TX, USA.", "authors": "Reinert\|Justin P\|JP\|;Cook\|Elizabeth A\|EA\|https://orcid.org/0000-0002-3496-9587", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/8755122519850477", "fulltext": null, "fulltext_license": null, "issn_linking": "1549-4810", "issue": "35(4)", "journal": "The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians", "keywords": "adverse drug reactions; anticonvulsants; medication safety; neurology; pharmacogenetics and pharmacogenomics", "medline_ta": "J Pharm Technol", "mesh_terms": null, "nlm_unique_id": "8504643", "other_id": null, "pages": "179-183", "pmc": null, "pmid": "34752516", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": "25495410;27651712;18821094;17386054;22429379;10718894;14791600;21449936;21428769;7249508;23882307;25933949;18490142;1379159;22528618;9276112;17362215;22424655;19153346;23108810;1430701;24926019", "title": "Oxcarbazepine-Induced Cutaneous Reaction in a Female of Mexican Ancestry.", "title_normalized": "oxcarbazepine induced cutaneous reaction in a female of mexican ancestry" }	[ { "companynumb": "PHHY2019US166036", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021014", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIGEMINAL NEURALGIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERCHOLESTEROLAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash morbilliform", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash papular", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "22.0", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "REINERT JP, COOK EA. OXCARBAZEPINE-INDUCED CUTANEOUS REACTION IN A FEMALE OF MEXICAN ANCESTRY. JOURNAL OF PHARMACY TECHNOLOGY. 2019?35(4):179-83", "literaturereference_normalized": "oxcarbazepine induced cutaneous reaction in a female of mexican ancestry", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190905", "receivedate": "20190723", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16619152, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "Acute respiratory distress syndrome, characterized by the Berlin criteria, is associated with a high mortality rate. Its treatment includes addressing the underlying etiology, general supportive measures, and achievement of effective oxygenation. New key data indicates that in a subset of patients, noninvasive ventilation techniques can be a therapeutic and equivalent alternative to traditional invasive ventilation. We present a rare case of ARDS triggered by nasal bupropion inhalation and effectively treated with noninvasive positive pressure ventilation resulting in complete resolution.", "affiliations": "Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Pulmonary/Critical Care, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.", "authors": "Al-Saiegh\|Yousif\|Y\|https://orcid.org/0000-0003-4579-8610;Spears\|Jenna\|J\|https://orcid.org/0000-0003-0182-7774;De Klerk\|Pieter S\|PS\|;Hitchings\|Joshua\|J\|;Lee\|Christopher\|C\|https://orcid.org/0000-0003-3851-9206;Mahr\|Tamara\|T\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2020/5107456", "fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420 2090-6439 Hindawi \n\n10.1155/2020/5107456\nCase Report\nA Rare Case of ARDS Caused by Bupropion Inhalation and Treated with Noninvasive Ventilation\nhttps://orcid.org/0000-0003-4579-8610Al-Saiegh Yousif [email protected]\n1\n https://orcid.org/0000-0003-0182-7774Spears Jenna \n1\n De Klerk Pieter S. \n1\n Hitchings Joshua \n1\n https://orcid.org/0000-0003-3851-9206Lee Christopher \n1\n Mahr Tamara \n2\n \n1Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA\n\n2Department of Pulmonary/Critical Care, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA\nAcademic Editor: Mabrouk Bahloul\n\n\n2020 \n28 5 2020 \n2020 510745629 1 2020 23 3 2020 Copyright © 2020 Yousif Al-Saiegh et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Acute respiratory distress syndrome, characterized by the Berlin criteria, is associated with a high mortality rate. Its treatment includes addressing the underlying etiology, general supportive measures, and achievement of effective oxygenation. New key data indicates that in a subset of patients, noninvasive ventilation techniques can be a therapeutic and equivalent alternative to traditional invasive ventilation. We present a rare case of ARDS triggered by nasal bupropion inhalation and effectively treated with noninvasive positive pressure ventilation resulting in complete resolution.\n==== Body\n1. Introduction\nAcute respiratory distress syndrome (ARDS) incorporates a cluster of clinical features including shortness of breath and tachypnea and is defined by the Berlin criteria as having an acute onset with the development of hypoxemia and bilateral pulmonary opacities on radiographic imaging [1]. There are many causes of ARDS; however, most often, it is triggered by infections, blood transfusions, direct lung injury, and toxins [2]. Treatment includes removal of the inciting cause, supportive therapy, and the attainment of sufficient blood oxygenation. Adequate oxygenation in ARDS is often achieved by endotracheal intubation and mechanical ventilation. Noninvasive positive pressure ventilation (NIPPV) has been less frequently indicated as an alternative form of adequate oxygenation. Typically, its use is focused and intended on preventing complications that are associated with invasive ventilation such as barotrauma, vocal cord injury, and ventilator-associated pneumonia [3].\n\nBupropion is an atypical oral antidepressant medication commonly used to treat depression, tobacco dependence, obesity, and hypoactive sexual disorder. Its mechanism of action involves the inhibition and reuptake of norepinephrine and dopamine which can induce a state of euphoria. Because of these effects, bupropion has been reported to be abused recreationally [4, 5]. We describe a case of ARDS induced by bupropion inhalation that was treated with NIPPV.\n\n2. Case Presentation\nA 30-year-old male with a past medical history significant for polysubstance abuse presented to the emergency department (ED) two hours after ingesting 90 mg of oxycodone and 30 mg of diazepam along with intranasal bupropion. On arrival, he complained of extreme fatigue, respiratory distress, and confusion.\n\nIn the ED, he was noted to be lethargic and short of breath. Initial vital signs revealed heart rate of 104 beats per minute, respiratory rate of 35 per minute, and O2 saturation of 75% on room air. Respiratory exam revealed diffuse bilateral coarse breath sounds on inspiration and expiration. His laboratory results were notable for a leukocytosis of 14.1 K, creatinine of 1.25 g/dl, lactate of 4.1, and an elevated procalcitonin level. Venous blood gas analysis showed a pH of 7.18 with a pCO2 of 51 mmHg. Chest X-ray (CXR) demonstrated diffuse bilateral alveolar infiltrates (Figure 1(a)). Computed tomography (CT) of the chest showed diffuse bilateral airspace disease characterized by groundglass and consolidative opacities with relative peripheral lung sparing and perihilar predominance (Figure 2). He received naloxone with mild improvement in mental status and was initiated on Bilevel Positive Airway Pressure (BiPAP) with an inspiratory positive airway pressure (IPAP) of 15 cm H2O, expiratory positive airway pressure (EPAP) of 5 cm H2O with 40% fraction of inspired oxygen (FiO2). Empiric broad spectrum antibiotics including vancomycin, cefepime, and metronidazole were initiated along with intravenous methylprednisolone 40 mg every 12 hours.\n\nInitially while on BIPAP, he remained tachypneic and tachycardic. His respiratory rate improved over the following 6 hours. He was gradually weaned off BiPAP to nasal cannula oxygen over the course of 36 hours while receiving ongoing corticosteroid and antibiotic therapy.\n\nRepeat CXR on hospital day #6 showed markedly improved bilateral airspace opacities (Figure 1(b)). After 6 days, he was discharged in stable condition without requiring supplemental oxygen.\n\n3. Discussion\nARDS is associated with a high mortality that has declined from over 50% to 30% over the last four decades [6, 7]. This is primarily due to implementation of lung-protective ventilation protocols and intensified research after formation of the National Heart, Lung, and Blood Institute (NHLBI) ARDS network [8, 9]. This case highlights a mild manifestation of ARDS as a result of bupropion inhalation, an exceedingly rare etiology.\n\nThe Food and Drug Administration (FDA) classifies bupropion as a psychiatric medication with low abuse potential [10]. However, several case reports and studies have indicated increasing recreational use of bupropion mostly intravenously or intranasally [11–13]. Lewis et al. conducted a review on bupropion inhalation in a total of 67 patients. Seizures were noted as a common adverse effect occurring in 30% of patients. Acute lung toxicity was not reported as a complication [14]. We were not able to find a second reported case of bupropion-inhalation-induced ARDS.\n\nEndotracheal intubation and mechanical ventilation are mostly required to ensure adequate oxygenation, but this was avoided in this patient as we maintained adequate oxygenation with BiPAP alone. NIPPV is advantageous in such patients as it does not expose them to the potential complications of invasive ventilation and may shorten their hospital length of stay [3]. There is, however, an ongoing debate concerning the most effective mode of NIPPV [15, 16]. Recent studies show that noninvasive ventilation can be used in mild cases of ARDS with acute nonhypercapnic hypoxemic respiratory failure [17]. In these cases, BiPAP via facemask is the most commonly used strategy [18]. Another approach with high-flow nasal cannula was shown to have a similar degree of treatment failure and incidence of subsequent intubation as BiPAP. High-flow nasal cannula, however, was associated with decreased 90-day mortality as compared to BiPAP [19]. A randomized, single-center trial by Pohlman et al. showed that delivering noninvasive ventilation via helmet instead of by facemask was associated with a significant reduction in intubations. There was also a decrease in intensive care unit length of stay and mortality at 90 days [20]. However, a subset analysis of the observational “LUNG-SAFE” study for patients with severe ARDS (defined as a PaO2/FiO2 ratio below 150 mmHg) showed increased mortality with noninvasive ventilation [21].\n\nPer our review, data on the use of noninvasive ventilation in the management of ARDS remains inconclusive and conflicting. NIPPV may decrease the incidence of ventilator-associated complications; however, given that its efficacy is not well established, patients with ARDS should still be treated in a critical care setting for close monitoring with invasive ventilation available on standby.\n\n4. Conclusion\nAdvances in the treatment of the underlying etiologies and improvement in mechanical ventilation strategies have led to a decrease in the overall mortality associated with ARDS. Despite these developments, it remains a diagnosis with an exceedingly high mortality. New emerging data indicates that NIPPV can be a beneficial and equivalent approach for a subset of patients with ARDS, although the optimal type of noninvasive ventilation and patient group that would benefit most is yet to be determined.\n\nConflicts of Interest\nAll authors declare no conflict of interest.\n\nFigure 1 (a) Single-view anterior-posterior chest X-ray on day #1 showed diffuse bilateral lung opacities. (b) Repeat single-view anterior-posterior chest X-ray on day #6 showed decreased airspace opacities.\n\nFigure 2 Contrast-enhanced computed tomography of the chest on day #2 shows diffuse bilateral airspace disease characterized by groundglass and consolidative opacities, with relative peripheral sparing and perihilar predominance. No pleural effusions or pneumothorax.\n==== Refs\n1 The ARDS Definition Task Force Acute respiratory distress syndrome: the Berlin definition JAMA 2012 307 2526 2533 10.1001/jama.2012.5669 2-s2.0-84862490519 22797452 \n2 Fan E. Brodie D. Slutsky A. S. Acute respiratory distress syndrome: advances in diagnosis and treatment JAMA 2018 319 7 698 710 10.1001/jama.2017.21907 2-s2.0-85042281861 29466596 \n3 Taha A. Larumbe-Zabala E. Abugroun A. Mohammedzein A. Naguib M. T. Patel M. Outcomes of noninvasive positive pressure ventilation in acute respiratory distress syndrome and their predictors: a national cohort Critical Care Research and Practice 2019 2019 8 8106145 10.1155/2019/8106145 2-s2.0-85072983506 31641538 \n4 Arias H. R. Is the inhibition of nicotinic acetylcholine receptors by bupropion involved in its clinical actions? The International Journal of Biochemistry & Cell Biology 2009 41 11 2098 2108 10.1016/j.biocel.2009.05.015 2-s2.0-70349267544 19497387 \n5 Langguth B. Hajak G. Landgrebe M. Unglaub W. Abuse potential of bupropion nasal insufflation: a case report Journal of Clinical Psychopharmacology 2009 29 6 618 619 10.1097/JCP.0b013e3181c09475 2-s2.0-72949087811 19910738 \n6 Milberg J. A. Davis D. R. Steinberg K. P. Hudson L. D. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993 JAMA 1995 273 4 306 309 10.1001/jama.1995.03520280052039 2-s2.0-0028798336 7815658 \n7 Ashbaugh D. G. Bigelow D. B. Petty T. L. Levine B. E. Acute respiratory distress in adults The Lancet 1967 2 7511 319 323 10.1016/s0140-6736(67)90168-7 4143721 \n8 Amato M. B. P. Barbas C. S. V. Medeiros D. M. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome The New England Journal of Medicine 1998 338 6 347 354 10.1056/NEJM199802053380602 2-s2.0-0032484956 9449727 \n9 Thompson B. T. Bernard G. R. ARDS network (NHLBI) studies: successes and challenges in ARDS clinical research Critical Care Clinics 2011 27 3 459 468 10.1016/j.ccc.2011.05.011 2-s2.0-79960143563 21742211 \n10 Substance abuse treatment for persons with HIV/AIDS 2000 Rockville Substance Abuse and Mental Health Services Administration (US) \n11 Stall N. Godwin J. Juurlink D. Bupropion abuse and overdose CMAJ 2014 186 13 p. 1015 10.1503/cmaj.131534 2-s2.0-84921626320 24778361 \n12 Stassinos G. L. Klein-Schwartz W. Bupropion \"abuse\" reported to US poison centers Journal of Addiction Medicine 2016 10 5 357 362 10.1097/ADM.0000000000000249 2-s2.0-84996508810 27504927 \n13 Starr P. Klein-Schwartz W. Spiller H. Kern P. Ekleberry S. E. Kunkel S. Incidence and onset of delayed seizures after overdoses of extended-release bupropion The American Journal of Emergency Medicine 2009 27 8 911 915 10.1016/j.ajem.2008.07.004 2-s2.0-70349185366 19857406 \n14 Lewis J. C. Sutter M. E. Albertson T. E. Owen K. P. Ford J. B. An 11-year review of bupropion insufflation exposures in adults reported to the California Poison Control System Clinical Toxicology 2014 52 9 969 972 10.3109/15563650.2014.969372 2-s2.0-84910091245 25308323 \n15 Messika J. Ben Ahmed K. Gaudry S. Use of high-flow nasal cannula oxygen therapy in subjects with ARDS: a 1-year observational study Respiratory Care 2015 60 2 162 169 10.4187/respcare.03423 2-s2.0-84930512185 25371400 \n16 Ou X. Hua Y. Liu J. Gong C. Zhao W. Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials CMAJ 2017 189 7 E260 E267 10.1503/cmaj.160570 2-s2.0-85014057578 28246239 \n17 Zhan Q. Sun B. Liang L. Early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial Critical Care Medicine 2012 40 2 455 460 10.1097/CCM.0b013e318232d75e 2-s2.0-84856216479 22020236 \n18 Kredel M. Bierbaum D. Lotz C. Kustermann J. Roewer N. Muellenbach R. M. Therapy of acute respiratory distress syndrome : survey of German ARDS centers and scientific evidence Anaesthesist 2015 64 4 277 285 10.1007/s00101-015-0010-1 2-s2.0-84937763236 25824000 \n19 Frat J. P. Thille A. W. Mercat A. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure The New England Journal of Medicine 2015 372 23 2185 2196 10.1056/NEJMoa1503326 2-s2.0-84930535780 25981908 \n20 Patel B. K. Wolfe K. S. Pohlman A. S. Hall J. B. Kress J. P. Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial JAMA 2016 315 22 2435 2441 10.1001/jama.2016.6338 2-s2.0-84974802607 27179847 \n21 Bellani G. Laffey J. G. Pham T. Noninvasive ventilation of patients with acute respiratory distress syndrome. Insights from the LUNG SAFE study American Journal of Respiratory and Critical Care Medicine 2017 195 1 67 77 10.1164/rccm.201606-1306OC 2-s2.0-85008690467 27753501\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2020()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "5107456", "pmc": null, "pmid": "32550027", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "24778361;4143721;22020236;31641538;27179847;25981908;27504927;21742211;29466596;19910738;25371400;19497387;9449727;25824000;28246239;7815658;25308323;27753501;19857406;22797452", "title": "A Rare Case of ARDS Caused by Bupropion Inhalation and Treated with Noninvasive Ventilation.", "title_normalized": "a rare case of ards caused by bupropion inhalation and treated with noninvasive ventilation" }	[ { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2021JUB00242", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "^INTRANASAL^", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AL?SAIEGH Y, SPEARS J, DE KLERK PS, HITCHINGS J, LEE C, MAHR T. 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{ "abstract": "Managing migraines complicated with medication overuse headaches and opioid-induced hyperalgesia can be challenging, especially within the geriatric and chronic pain population. A 65-year-old woman with a degenerative spine condition and chronic migraine headaches, along with other comorbidities, was admitted to the geriatric psychiatry unit for extreme mood swings and paranoia. Prior to admission, she had been taking extended-release morphine sulfate twice daily for more than a month and was unable to determine triggers to her frequent migraine headaches. She had a history of medication overuse and severe migraine episodes within 4 weeks prior to admission. This case report reviews the challenges of treating a geriatric patient with probable chronic migraines in addition to other pain conditions and comorbidities.", "affiliations": "Doctor of Pharmacy, University of Maryland School of Pharmacy, Baltimore, Maryland.;(Corresponding author) Clinical Pharmacist, Sheppard Pratt Health System, Towson, Maryland, [email protected].", "authors": "Bach\|Linda Lu\|LL\|;Goga\|Joshana\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.9740/mhc.2016.05.154", "fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2016.05.154mhcl-06-02-05Customer: MHC-D-14-00048R3Open SubmissionsManagement of migraine headaches in a chronic pain patient: A case report Bach Linda Lu PharmD1Goga Joshana PharmD, BCPP2\n1 Doctor of Pharmacy, University of Maryland School of Pharmacy, Baltimore, Maryland\n\n2 (Corresponding author) Clinical Pharmacist, Sheppard Pratt Health System, Towson, Maryland, [email protected]\n6 2016 6 5 2016 6 3 154 158 © 2016 CPNP.2016The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Managing migraines complicated with medication overuse headaches and opioid-induced hyperalgesia can be challenging, especially within the geriatric and chronic pain population. A 65-year-old woman with a degenerative spine condition and chronic migraine headaches, along with other comorbidities, was admitted to the geriatric psychiatry unit for extreme mood swings and paranoia. Prior to admission, she had been taking extended-release morphine sulfate twice daily for more than a month and was unable to determine triggers to her frequent migraine headaches. She had a history of medication overuse and severe migraine episodes within 4 weeks prior to admission. This case report reviews the challenges of treating a geriatric patient with probable chronic migraines in addition to other pain conditions and comorbidities.\n\nKeywords\nmigrainemedication overuse headacheopioid-induced hyperalgesiachronic paingeriatricopioid\n==== Body\nIntroduction\nMigraines are a type of headache associated with nausea, vomiting, and/or sensitivity to light. The headache can be potentiated by abnormal brain activity triggered by caffeine withdrawal, changes in sleep patterns, loud noises, bright lights, various foods, stress, or anxiety. Currently, there is no cure for migraine headaches. The goal of treatment is to manage symptoms and prevent recurrence.1 Guidelines exist for preventing recurring migraines and treating acute attacks, but patients with coexisting chronic pain may pose additional challenges to these treatments. These patients are at risk for medication overuse headaches (MOHs) and opioid-induced hyperalgesia (OIH) due to regular intake of acute or chronic analgesics.\n\nWhen managing migraines, treatment approach is similar for chronic (≥15 migraines per month for more than 3 months on ≥8 days per month) and episodic migraines (<15 migraines per month); both include prophylactic therapy and acute therapy.2 The American Academy of Neurology guidelines for migraine recurrence prevention lists several medications shown to be effective in migraine prevention3:\n\nAntiepileptic drugs: topiramate and valproic acid and derivatives\n\nBeta-blockers: metoprolol, propranolol, and timolol\n\nTriptans: for short-term menstrually associated migraine prevention\n\nIn clinical practice, first-line prophylactic medications for chronic migraine include the following4:\n\nPropanolol\n\nAmitriptyline\n\nTopiramate\n\nValproic acid and derivatives (second line in women due to teratogenicity)\n\nIn 2 randomized, double-blinded, placebo-controlled trials, topiramate was found to be effective and well-tolerated in patients with chronic migraine with or without presence of medication overuse.5,6 Botulinum toxin injections may also be an option in reducing migraine attacks if they occur more than 15 days a month.1 OnabotulinumtoxinA has been approved by the US Food and Drug Administration to treat chronic migraine.\n\nFor acute treatment options, first-line therapies include the following7:\n\nAcetaminophen/aspirin/caffeine combination analgesic\n\nNonsteroidal anti-inflammatory drugs (eg, ibuprofen and naproxen)\n\nTriptans (eg, sumatriptan)\n\nTriptan/nonsteroidal anti-inflammatory drugs combination analgesic (eg, sumatriptan/naproxen)\n\nAccording to the International Headache Society, MOH is characterized by (1) a headache present for ≥15 days per month with a preexisting headache disorder, (2) regular overuse for more than 3 months of one or more drugs taken for acute and/or symptomatic treatment of headache, and (3) a headache developed or markedly worsened during medication overuse (ie, ≥15 days per month of simple analgesics and combination acute medications or ≥10 days per month of triptans, ergotamines, opioids, and/or combination analgesics).2,8 Risk factors for MOH include previous primary headaches (eg, migraine and tension headaches) in addition to a history of substance abuse, regular use of tranquilizers, or an increased score on the Hospital Anxiety and Depression Scale.8 Depression and anxiety are also common coexisting conditions in patients with MOH, which may be related to the frequency of headaches these patients experience. Chronic pain medication therapies, especially with opioids, have the potential to trigger MOH as well as induce migraines and other types of headaches.\n\nFor people receiving long-term opioid therapy, pain management can be limited not only by opioid tolerance but also by OIH, which is characterized by increased pain sensitization as a result of increased or long-term opioid exposure.9,10 There are multiple theories on the cause of OIH, but the most studied mechanism is the increased activation of N-methyl-D-aspartate (NMDA) receptors by opioids, which can cause more pain impulse transmissions and affect the amount of pain sensitivity in both acute and chronic pain states.11,12 According to a prospective study, some patients on oral morphine therapy experienced both analgesic tolerance and hyperalgesia within 1 month of initiating therapy.10 In addition, the occurrence of OIH may be due to accumulation of toxic opioid metabolites, such as morphine-3-glucuronide, which may act as NMDA agonists and lead to other opioid hyperexcitability effects, such as delirium and seizures.11,13,14 Clinicians should suspect OIH if treatment effect appears to decline in absence of disease progression or if there are unexplained pain reports unrelated to the site of injury.15 Treatments for OIH include the following:\n\nReducing opioid exposure by reducing the dose or removing it from therapy11,16,17\n\nOpioid rotation or switching to a different opioid11,17,18\n\nAdding an NMDA receptor antagonist (eg, methadone, cyclooxygenase-2 inhibitors)11,17,19\n\nAdding alpha-2 receptor agonists (eg, clonidine)17\n\nManaging migraines in patients complicated with MOH and OIH can be challenging, especially in the geriatric population, because the prevalence of persistent pain increases with age and most geriatric patients have significant pain problems that are not adequately relieved.20 Opioids are the “gold standard” for therapeutic management of chronic pain, and with many of the elderly being treated for chronic pain, the geriatric population is at higher risk of OIH.9 A study of 2 health plans found that from 1997 to 2005 the total percentage increase in prevalence of long-term opioid use ranged from 61% to 135%; women aged 65 years or older had the highest prevalence in 2005.21 In the Group Health cooperative study from 2005, 44.1% of those aged 65 years or older were on long-term schedule II opioid treatment.21 Also, from 1998 to 2006, regular opioid use increased with age, and the prevalence of regular opioid use in those aged 70 years or older was 3.4% by 2006.22 Arthritis and back pain were the most common chronic conditions found among regular users of opioids, and most of these users had more than one pain condition that needed treatment.23 The following case report reviews the challenges of treating a geriatric patient with probable chronic migraine in addition to other patient-related variables.\n\nCase Description\nThe patient, a 65-year-old woman, was admitted to the geriatric psychiatry inpatient unit due to depression, severe anxiety, paranoia, delirium, and extreme mood swings. She reported poor sleep and poor appetite and had expressed problems with concentration. She also reported painful migraines and had been admitted to a community hospital for a migraine episode prior to admission. When asked about headache triggers, the patient noticed that caffeine, particularly coffee, and loud voices were possible triggers but otherwise had not noticed any other trigger patterns for her chronic migraines. At least 2 reports of migraine headaches coinciding with overmedication were found within the 2 weeks prior to admission in external records (Table 1). Her relevant past medical history included depression, frequent migraines, arthritis, and chronic neck and spine pain from her degenerative spine condition. Her family history included migraines in her maternal grandmother, and her social history included substance abuse with opioids.\n\nTABLE 1: Pharmacy medication records 3 months prior to admission\n\nThe patient reported being compliant with medications, though she stated that she had decreased her topiramate prior to admission due to her concern about weight loss. The patient had been seeing a psychotherapist and psychiatrist but failed to follow up after relocating and facing financial burden. The patient last saw her psychiatrist about a year prior to admission, and all her psychiatric medications were being prescribed by her neurologist. She also had a pain specialist who at first prescribed extended-release morphine sulfate 30 mg twice daily for her chronic spine pain but then switched her to oxycodone 5 mg 5 times daily prior to admission. All medications dispensed 3 months prior to admission came from 2 pharmacies.\n\nAccording to the patient, her current life stressors included finances, adjusting to her new home, and lack of sleep. During the first interview, the patient reported that she was addicted to morphine and was withdrawing from it. She also reported not abusing her medications and only following the instructions on the medication labels. Her husband and primary care physician did not believe she was abusing her medications.\n\nFor migraine treatment, the patient reported that she had tried beta blockers in the past and those did not work for her. The patient also reported that her divalproex delayed release was discontinued and that acetaminophen “spiked” her liver enzymes. Additionally, the patient mentioned that her neurologist said she was a candidate for botulinum toxin injection and before admission had scheduled her to have a treatment within the next couple of months. The patient admitted to consuming caffeinated sodas around the clock prior to admission.\n\nDuring admission, the patient's problem list included bipolar II disorder, anxiety, insomnia, migraines, chronic spinal pain, neuropathic pain, arthritis, hypertension, hypothyroidism, and gastroesophageal reflux disease. Bipolar II disorder was a new diagnosis during this admission, and relevant medications were added or increased in dose to minimize side effects and optimize overall therapy. Reports were unclear as to whether the patient's frequent migraines existed prior to medication overuse or if medication overuse caused the frequent migraines. Regardless, the patient was converted to oxycodone, topiramate was titrated to 100 mg daily for migraine prophylaxis, and the patient was counseled to reduce caffeine consumption. Also, methylphenidate was originally not included in overall therapy due to risk of worsening migraines but was eventually added at a low dose to improve patient affect and energy. Neuropathic pain was another new diagnosis during admission, and thus gabapentin was added into overall therapy. Toward the time of discharge, the patient reported worsening arthritis that affected her sleep, and naproxen was prescribed as needed to address the pain and improve sleep. The patient's overall pain ranged between 3 and 8 out of 10; however, most scores hovered around 5 of 10 with 10 being the worst pain imaginable.\n\nHer vital signs were all within normal limits and renal function remained normal. The medications prescribed upon discharge after 3 weeks of admission are shown in Table 2.\n\nTABLE 2: Discharge medications\n\nThe patient was referred for follow-up with her neurologist and a new pain specialist upon discharge.\n\nDiscussion\nIn controlling migraine recurrence, this patient's modifiable risk factors included depression, anxiety, stress triggers, previous chronic caffeine exposure, medication overuse, and chronic pain. Previous longitudinal studies support a bidirectional relationship between depression and migraines.24 Also, the effects of depression and anxiety can worsen migraine symptoms and frequency. Stress can trigger headaches, and in this case the patient's financial and living situation, lack of sleep, and other stressors may have contributed to her chronic migraines. The patient admitted to consuming caffeinated sodas around the clock prior to admission, which can lead to withdrawal from chronic consumption and trigger migraine headaches. Additionally, medication overuse with barbiturates or opiates can cause rebound headache and OIH, and in this patient's case, she had been taking extended-release morphine sulfate twice daily for more than a month prior to admission. Finally, the patient continued to have chronic pain from her degenerative spine condition, which was not adequately managed and potentially exaggerated from OIH. Managing these risk factors would improve this patient's frequent migraines.\n\nDuring admission, the treatment focused on managing the patient's psychiatric conditions, her overall pain, and her frequent migraines. Because morphine sulfate is known to metabolize into codeine and morphine-3-glucuronide and the patient was delirious prior to admission while being on morphine sulfate, she was switched from extended-release morphine sulfate to oxycodone to reduce probable MOH, opioid toxicity, and OIH.25 Since then, the patient has had reduced symptoms of delirium, and her overall pain has remained relatively stable around 5 out of 10. With the new onset of neuropathic pain, gabapentin was also added and adequately managed this pain without worsening other therapies. Finally, naproxen was given as needed to relieve worsening arthritic pain, and it adequately managed her arthritis without inducing additional headaches. Because the patient still had unrelieved moderate-level pain in her neck and back, the patient was told to follow up with her pain specialist and neurologist to manage her pain and frequent migraines.\n\nWhile the patient was being treated for anxiety and depression, her migraines were managed according to current migraine guidelines. At least 2 randomized placebo-controlled trials support the use of topiramate for chronic migraine prophylaxis compared with the lower-quality evidence for use of valproic acid and derivatives.4-6 The patient also reported having been discontinued on divalproex and taking topiramate before admission. After multiple interviews, and considering the patient's overall condition and medication history, the patient agreed to take topiramate at bedtime for migraine recurrence prevention and sumatriptan for acute migraine attacks. She was also advised to record any migraine triggers so that she could identify patterns and try to avoid them. Finally, the patient was counseled on how and why she takes her medications and the risks and side effects involved with each one, especially with oxycodone and topiramate as she has a history of medication overuse and self-decreased dosing. Since then, the patient has worked on identifying more migraine triggers and appeared to have better affect as well as reduced severity and frequency of migraines.\n\nEven though methylphenidate can potentially worsen migraines, the patient reported improved concentration and productivity at a low dose without worsening migraines. The patient also achieved her original weight as overall mood, affect, and pain improved. Although the patient was improving in most aspects of therapy, however, her migraines and overall pain were not adequately relieved. In conclusion, this case report discusses the challenges of managing migraines when chronic pain management and other conditions are involved. 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Available from: http://www.micromedexsolutions.com.proxy-hs.researchport.umd.edu/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/FFB3C8/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/14FFE9/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.DisplayDrugdexDocument?docId=0516&contentSetId=31&title= Morphine+Sulfate&servicesTitle=Morphine+Sulfate&topicId= pharmacokineticsSection .\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2168-9709", "issue": "6(3)", "journal": "The mental health clinician", "keywords": "chronic pain; geriatric; medication overuse headache; migraine; opioid; opioid-induced hyperalgesia", "medline_ta": "Ment Health Clin", "mesh_terms": null, "nlm_unique_id": "101728585", "other_id": null, "pages": "154-158", "pmc": null, "pmid": "29955463", "pubdate": "2016-06", "publication_types": "D002363:Case Reports", "references": 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PRN", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paranoia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mood swings", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperaesthesia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuralgia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Delirium", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Medication overuse headache", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bipolar II disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BACH LL, GOGA J. MANAGEMENT OF MIGRAINE HEADACHES IN A CHRONIC PAIN PATIENT: A CASE REPORT. MENT HEALTH CLIN. 2016?6(3):154?8", "literaturereference_normalized": "management of migraine headaches in a chronic pain patient a case report", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180706", "receivedate": "20180706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15117384, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]
{ "abstract": "Emergency physicians (EPs) can use bedside ultrasound to diagnosis of intraabdominal free fluid in a variety of clinical scenarios.The purpose of this study is to review the sonographic appearance of intraabdominal free fluid and incidence of spontaneous splenic rupture. An EP used bedside ultrasound to diagnose spontaneous splenic rupture in a patient who had received tissue plasminogen activator for suspected acute ischemic stroke. Bedside ultrasound by a physician trained in basic ultrasound and the focused assessment with sonography for trauma can diagnose intraabdominal free fluid, facilitating appropriate and more rapid consultation, advanced imaging, and treatment.", "affiliations": "Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].;Brigham and Women's Hospital, Boston, MA. Electronic address: [email protected].;Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].;Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].;Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].", "authors": "Genthon\|Alissa\|A\|;Frasure\|Sarah\|S\|;Kinnaman\|Karen\|K\|;Huang\|Calvin\|C\|;Noble\|Vicki\|V\|", "chemical_list": "D010959:Tissue Plasminogen Activator", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "32(12)", "journal": "The American journal of emergency medicine", "keywords": null, "medline_ta": "Am J Emerg Med", "mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D006470:Hemorrhage; D006801:Humans; D019095:Point-of-Care Systems; D013154:Spleen; D013158:Splenic Diseases; D020521:Stroke; D010959:Tissue Plasminogen Activator; D014463:Ultrasonography", "nlm_unique_id": "8309942", "other_id": null, "pages": "1553.e1-2", "pmc": null, "pmid": "25303848", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration.", "title_normalized": "bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration" }	[ { "companynumb": "US-ROCHE-1521220", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC STROKE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTILYSE" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Splenic haemorrhage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GENTHON A, FRASURE S, KINNAMAN K, HUANG C, AND NOBLE V. BEDSIDE ULTRASOUND DIAGNOSIS OF A SPONTANEOUS SPLENIC HEMORRHAGE AFTER TISSUE PLASMINOGEN ACTIVATOR ADMINISTRATION. AMERICAN JOURNAL OF EMERGENCY MEDICINE 2014 DEC 01;32 (12):1553.E1-1553.E2.", "literaturereference_normalized": "bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150121", "receivedate": "20150116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10715234, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "Secondary lymphohistiocytosis is a severe inflammatory condition characterized by uncontrolled inflammatory response hyperactivation of antigen-presenting cells, hemophagocytosis, cytopenias, and multiorgan failure, and is secondary to subjacent pathologies such as cancer, infection, or immune disease. Standard treatment includes chemotherapy; however, this is not always possible or safe. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor can reduce inflammation and cytokine activity and has been used in refractory cases and first-line treatment. Here, we present a 35-year-old patient with HIV infection and secondary lymphohistiocytosis due to CMV/EBV infection who was successfully treated with ruxolitinib as first-line therapy. He rapidly showed clinical and biochemical improvement and transfusion independence without complications.", "affiliations": "Hospital General de Tijuana, Secretaría de Salud de Baja California, Avenida Centenario 10851, Zona Río, CP 22680, Tijuana, Baja California, Mexico. [email protected].;Hospital General Regional 20, Instituto Mexicano del Seguro Social, Boulevard Díaz Ordaz y Lázaro Cárdenas, La Meza, CP 22450, Tijuana, Baja California, Mexico.", "authors": "Gálvez Acosta|Sergio|S|;Javalera Rincón|Mariana|M|", "chemical_list": "D016207:Cytokines; D018836:Inflammation Mediators; D000075242:Janus Kinase Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib", "country": "Japan", "delete": false, "doi": "10.1007/s12185-020-02882-1", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "112(3)", "journal": "International journal of hematology", "keywords": "CMV/EBV infection; HIV infection; Ruxolitinib; Secondary hemophagocytic lymphohistiocytosis", "medline_ta": "Int J Hematol", "mesh_terms": "D000328:Adult; D016207:Cytokines; D003586:Cytomegalovirus Infections; D020031:Epstein-Barr Virus Infections; D015658:HIV Infections; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators; D000075242:Janus Kinase Inhibitors; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D016896:Treatment Outcome", "nlm_unique_id": "9111627", "other_id": null, "pages": "418-421", "pmc": null, "pmid": "32285358", "pubdate": "2020-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Ruxolitinib as first-line therapy in secondary hemophagocytic lymphohistiocytosis and HIV infection.", "title_normalized": "ruxolitinib as first line therapy in secondary hemophagocytic lymphohistiocytosis and hiv infection" }

[ { "companynumb": "NVSC2020MX141725", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "013422", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypophagia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hallucination", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cachexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Serum ferritin increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhagic ascites", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemophagocytic lymphohistiocytosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GALVEZ AS, JAVALERA RM,. RUXOLITINIB AS FIRST-LINE THERAPY IN SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND HIV INFECTION. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2020", "literaturereference_normalized": "ruxolitinib as first line therapy in secondary hemophagocytic lymphohistiocytosis and hiv infection", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20200527", "receivedate": "20200527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17827993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "Abnormalities of the upper airway anatomy are an underrecognized cause of obstructive sleep apnea. We present a unique case of a 51-year-old man with episodic sleep-maintenance insomnia and oromandibular dystonia requiring botulinum toxin injections of the temporalis and masseter muscles. He underwent multiple sleep studies and was found to have obstructive sleep apnea temporally associated with the severity of dystonia symptoms and dosing of botulinum toxin.", "affiliations": "Scripps Health, San Diego, California.;VA Greater Los Angeles Healthcare, Los Angeles, California.;VA Greater Los Angeles Healthcare, Los Angeles, California.;VA Greater Los Angeles Healthcare, Los Angeles, California.", "authors": "Hsu|Nancy|N|;Hsieh|Caleb|C|;Thomas|Aaron|A|;Chang|Melisa|M|", "chemical_list": "D001905:Botulinum Toxins", "country": "United States", "delete": false, "doi": "10.5664/jcsm.8454", "fulltext": null, "fulltext_license": null, "issn_linking": "1550-9389", "issue": "16(7)", "journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine", "keywords": "botulinum toxin; dystonic disorders; insomnia; obstructive sleep apnea", "medline_ta": "J Clin Sleep Med", "mesh_terms": "D001905:Botulinum Toxins; D004421:Dystonia; D006801:Humans; D008297:Male; D008875:Middle Aged; D017286:Polysomnography; D020181:Sleep Apnea, Obstructive", "nlm_unique_id": "101231977", "other_id": null, "pages": "1209-1212", "pmc": null, "pmid": "32248896", "pubdate": "2020-07-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "17882462;11966340;30604200;26866500;18250211;21992649;23666585;19960649;1643688;17503232", "title": "Obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin.", "title_normalized": "obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin" }

[ { "companynumb": "US-MERZ PHARMACEUTICALS GMBH-20-01497", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BOTULINUM TOXIN TYPE A" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "125360", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OROMANDIBULAR DYSTONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOTULINUM TOXIN TYPE A" } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sleep apnoea syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HSU N, HSIEH C, THOMAS A, CHANG M. OBSTRUCTIVE SLEEP APNEA DUE TO OROMANDIBULAR DYSTONIA AND TREATED WITH BOTULINUM TOXIN. J CLIN SLEEP MED. 2020?.", "literaturereference_normalized": "obstructive sleep apnea due to oromandibular dystonia and treated with botulinum toxin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200710", "receivedate": "20200710", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18010838, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]

{ "abstract": "BACKGROUND\nAmlodipine is a racemic mixture of (R)- and (S)-enantiomers. It has been suggested that removing the therapeutically inactive (R)-enantiomer will reduce adverse events while preserving the agent's efficacy. Women experience more adverse effects from amlodipine.\n\n\nOBJECTIVE\nThis exploratory study compared the amount of pedal edema experienced by female Korean patients with mild to moderate hypertension when receiving S(-)-amlodipine nicotinate compared with amlodipine besylate.\n\n\nMETHODS\nThis study was a 12-week, multicenter, randomized, double-blind, active-controlled, Phase IV clinical trial. Female patients with mild to moderate hypertension were randomly assigned to receive either S(-)-amlodipine nicotinate 2.5 to 5 mg once daily or amlodipine besylate 5 to 10 mg once daily for 12 weeks. The primary objective was to compare the change in ankle-foot volume quantified by using a water displacement method after 12 weeks of therapy. The secondary objectives were to compare the changes in mean sitting systolic and diastolic blood pressures. Safety assessment included monitoring all laboratory tests, adverse events (AEs), serious AEs, and possible relation to the study medication.\n\n\nRESULTS\nOf the 38 patients enrolled, 17 patients in each group were eligible for final analysis. In the S(-)-amlodipine nicotinate group, the mean ankle-foot volume at baseline was 1056.91 (98.15) mL, and volume after 12 weeks of treatment was 1016.68 (158.37) mL, a decrease of 40.24 (110.05) mL. In the amlodipine besylate group, mean ankle-foot volume at baseline was 1037.56 (158.30) mL, and volume after treatment was 1067.59 (152.54) mL, an increase of 30.03 (69.59) mL. There was a significant difference in the change of ankle-foot volume between the 2 groups (-70.26 mL [95% CI, -134.60 to -5.94], P = 0.028). After 12 weeks, the mean changes in sitting systolic blood pressure from baseline were not significantly different between the 2 groups (-21.82 [8.76] vs -26.82 [11.89] mm Hg; P = 0.172). Changes in mean sitting diastolic blood pressure also were not significant (-14.71 [6.94] vs -10.88 [5.81] mm Hg; P = 0.091). One patient in each group had facial edema, and another patient in the amlodipine besylate group had facial flushing. Overall, there was no significant difference in drug-related AEs between the 2 groups (P = 0.999).\n\n\nCONCLUSIONS\nThese female Korean patients with hypertension taking S(-)-amlodipine nicotinate had less ankle edema, with no significant difference in BP-lowering efficacy, compared with those taking amlodipine besylate. S(-)-amlodipine nicotinate may be a suitable alternative for patients intolerant to amlodipine besylate. (Clinical Research Information Service: CRiS, KCT0000450).", "affiliations": "Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.", "authors": "Oh|Gyu-Chul|GC|;Lee|Hae-Young|HY|;Kang|Hyun-Jae|HJ|;Zo|Joo-Hee|JH|;Choi|Dong-Ju|DJ|;Oh|Byung-Hee|BH|", "chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; C519553:amlodipine nicotinate; D017311:Amlodipine; D009525:Niacin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0149-2918", "issue": "34(9)", "journal": "Clinical therapeutics", "keywords": null, "medline_ta": "Clin Ther", "mesh_terms": "D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D001794:Blood Pressure; D002121:Calcium Channel Blockers; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004487:Edema; D005260:Female; D005500:Follow-Up Studies; D005528:Foot; D006801:Humans; D006973:Hypertension; D008875:Middle Aged; D009525:Niacin; D056910:Republic of Korea; D013237:Stereoisomerism", "nlm_unique_id": "7706726", "other_id": null, "pages": "1940-7", "pmc": null, "pmid": "22925988", "pubdate": "2012-09", "publication_types": "D017429:Clinical Trial, Phase IV; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Quantification of pedal edema during treatment with S(-)-amlodipine nicotinate versus amlodipine besylate in female Korean patients with mild to moderate hypertension: a 12-week, multicenter, randomized, double-blind, active-controlled, phase IV clinical trial.", "title_normalized": "quantification of pedal edema during treatment with s amlodipine nicotinate versus amlodipine besylate in female korean patients with mild to moderate hypertension a 12 week multicenter randomized double blind active controlled phase iv clinical trial" }

[ { "companynumb": "KR-ALKEM LABORATORIES LIMITED-KR-ALKEM-2022-01991", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078925", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 TO 10 MG ONCE DAILY FOR 12 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Oh GC, Lee HY, Kang HJ, Zo JH, et al. Quantification of pedal edema during treatment with S(-)-amlodipine nicotinate versus amlodipine besylate in female Korean patients with mild to moderate hypertension: a 12-week, multicenter, randomized, double-blind, active-controlled, phase IV clinical trial. Clin Ther. 2012;34(9):1940-7", "literaturereference_normalized": "quantification of pedal edema during treatment with s amlodipine nicotinate versus amlodipine besylate in female korean patients with mild to moderate hypertension a 12 week multicenter randomized double blind active controlled phase iv clinical trial", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20220623", "receivedate": "20220623", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20997364, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "Breast cancer patients treated with adjuvant chemotherapy regimens containing alkylating agents and anthracyclines are at an increased risk for secondary myeloid malignancies, either acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Complex genomic changes (karyotypes and/or gene amplification) accompany the development of the secondary neoplasms. Here we present a unique case of a breast cancer patient who developed secondary AML within 18 months of treatment with trastuzumab, pertuzumab, docetaxel, carboplatin (TCHP) and radiation. Leukemia cells had catastrophic alterations in chromosomes 8, 11, and 17. Genetic abnormalities in the leukemia cells included amplification of MYC and KMT2A as double minutes, and deletion and mutational inactivation of TP53 Concurrent amplification of different genes at different levels and on different double minutes, we have named \"double minute heterogeneity.\" Clinically, this case highlights the need to identify genes amplified in secondary myeloid malignancies by cytogenomic microarray (CMA) analysis since these may have therapeutic implications.", "affiliations": "Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA. Electronic address: [email protected].;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.;Department of Pathology, and Division of Hematology and Oncology, Department of Medicine, UT Southwestern Medical Center, Dallas, USA.", "authors": "Koduru|Prasad|P|;Chen|Weina|W|;Haley|Barbara|B|;Ho|Kevin|K|;Oliver|Dwight|D|;Wilson|Kathleen|K|", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": "10.1016/j.cancergen.2019.08.001", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "238()", "journal": "Cancer genetics", "keywords": "Amplification; Breast cancer; Double minutes; KMT2A; MYC; Secondary AML", "medline_ta": "Cancer Genet", "mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged; D016609:Neoplasms, Second Primary", "nlm_unique_id": "101539150", "other_id": null, "pages": "69-75", "pmc": null, "pmid": "31425928", "pubdate": "2019-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia.", "title_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia" }

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CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA.. CANCER GENETICS. 2019?238:69-75", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190905", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16776296, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-FRESENIUS KABI-FK201909995", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IDARUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065440", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDARUBICIN HYDROCHLORIDE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16806759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-SA-2019SA236573", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QCY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": "811", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IDARUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDARUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QCY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": "811", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QCY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": "811", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, QCY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": "811", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pallor", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Granulocytes abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Petechiae", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Chromosomal mutation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myeloblast percentage increased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K.. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190906", "receivedate": "20190827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16748039, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-MYLANLABS-2019M1084594", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077998", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER-GENET 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16809552, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "US-DRREDDYS-USA/USA/19/0113873", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204193", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chromosomal mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75. DOI: 10.1016/J.CANCERGEN.2019.08.001.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191016", "receivedate": "20190904", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16770732, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-FRESENIUS KABI-FK201909919", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENETICS. 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16806780, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-220754", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77926", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENET. 2019?238:69?75", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200914", "receivedate": "20190918", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16821135, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" }, { "companynumb": "US-ACCORD-153452", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "206775", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "201195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201508", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chromosomal mutation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201701" } }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER GENET. 2019 AUG 6?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190913", "receivedate": "20190907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16783481, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-TEVA-2019-US-1108673", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYUREA" }, "drugadditional": null, 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null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUMOUR LYSIS SYNDROME", 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PERTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203551", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED 6 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACOGEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RASBURICASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUMOUR LYSIS SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RASBURICASE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KODURU P, CHEN W, HALEY B, HO K, OLIVER D, WILSON K. CYTOGENOMIC CHARACTERIZATION OF DOUBLE MINUTE HETEROGENEITY IN THERAPY RELATED ACUTE MYELOID LEUKEMIA. CANCER-GENET 2019?238:69-75.", "literaturereference_normalized": "cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190927", "receivedate": "20190917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16818621, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" } ]

{ "abstract": "Background: Epstein-Barr virus (EBV) infection is associated with significant morbidity and mortality in renal transplant (RT) recipients. The spectrum of illness ranges from infectious mononucleosis (IM) to post-transplant lymphoproliferative disorder (PTLD). In association with clinical signs and symptoms, virus-specific serology and heterophile antibody tests are widely used in confirming the diagnosis of IM in the general population. However, these tests may have a limited role in immunosuppressed RT recipients from seropositive donor, especially in children who were EBV-seronegative prior to the transplant. The aim of this study is to evaluate the utility of these tests in the early diagnosis of IM in this subset of patients. Methods: This is a case study with a review of literature. Results: Here, we present a 14-year-old male with hemophilia B who presented with fever, fatigue, sore throat, palatal petechial rash, exudative tonsillitis and cervical lymphadenopathy 3 months post-RT. He was EBV seronegative prior to RT and received a deceased donor kidney transplant from a seropositive donor. Induction was done with Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. Initial heterophile antibody test (monospot) was negative, but became positive at 5 months and remained positive at 9 months follow-up post-RT. EBV viral capsid antigens (VCA) IgM and IgG, early antigen (EA) and nuclear antigen (EBNA) were all negative at the time of presentation. VCA IgM and IgG both became positive at 5 months and peaked at 9 months follow-up, however the EA and EBNA remained negative. EBV viral load as measured by polymerase chain reaction (PCR) was negative for the first 3 months post-RT but became positive at presentation, peaked at 6 months and started declining thereafter. Peripheral blood smear examination showed no absolute and atypical lymphocytosis. Cytomegalovirus PCR in the blood and throat culture for streptococcus were negative. There was no splenomegaly. He was managed conservatively with intravenous fluids, bed rest, antipyretics and reduction of immunosuppression. Conclusions: EBV serological markers have a limited role in the early diagnosis of EBV-IM following RT in prior seronegative children. Initial heterophile antibody test may also be negative, and hence a repeat test may be necessary. Once becoming positive, the VCA IgM may remain persistently elevated for prolonged duration. In addition to the suppressed cellular immunity secondary to immunosuppression, humoral response to viral infections is also delayed in transplant recipients, especially in the early transplant period. Hence, routine monitoring with PCR is superior to serology in diagnosing IM early and monitoring the EBV infection post-RT for timely evaluation and management.", "affiliations": "Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.;Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.;Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.;Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.", "authors": "Byrne|Alexandra|A|;Bush|Rachel|R|;Johns|Felicia|F|;Upadhyay|Kiran|K|0000-0002-8441-0220", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/medicines7040021", "fulltext": "\n==== Front\nMedicines (Basel)\nMedicines (Basel)\nmedicines\nMedicines\n2305-6320 MDPI \n\n10.3390/medicines7040021\nmedicines-07-00021\nCase Report\nLimited Utility of Serology and Heterophile Test in the Early Diagnosis of Epstein–Barr Virus Mononucleosis in a Child after Renal Transplantation\nByrne Alexandra 1 Bush Rachel 2 Johns Felicia 2 https://orcid.org/0000-0002-8441-0220Upadhyay Kiran 2* 1 Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA\n2 Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA\n* Correspondence: [email protected]; Tel.: +352-273-9180\n22 4 2020 \n4 2020 \n7 4 2102 4 2020 20 4 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Epstein–Barr virus (EBV) infection is associated with significant morbidity and mortality in renal transplant (RT) recipients. The spectrum of illness ranges from infectious mononucleosis (IM) to post-transplant lymphoproliferative disorder (PTLD). In association with clinical signs and symptoms, virus-specific serology and heterophile antibody tests are widely used in confirming the diagnosis of IM in the general population. However, these tests may have a limited role in immunosuppressed RT recipients from seropositive donor, especially in children who were EBV-seronegative prior to the transplant. The aim of this study is to evaluate the utility of these tests in the early diagnosis of IM in this subset of patients. Methods: This is a case study with a review of literature. Results: Here, we present a 14-year-old male with hemophilia B who presented with fever, fatigue, sore throat, palatal petechial rash, exudative tonsillitis and cervical lymphadenopathy 3 months post-RT. He was EBV seronegative prior to RT and received a deceased donor kidney transplant from a seropositive donor. Induction was done with Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. Initial heterophile antibody test (monospot) was negative, but became positive at 5 months and remained positive at 9 months follow-up post-RT. EBV viral capsid antigens (VCA) IgM and IgG, early antigen (EA) and nuclear antigen (EBNA) were all negative at the time of presentation. VCA IgM and IgG both became positive at 5 months and peaked at 9 months follow-up, however the EA and EBNA remained negative. EBV viral load as measured by polymerase chain reaction (PCR) was negative for the first 3 months post-RT but became positive at presentation, peaked at 6 months and started declining thereafter. Peripheral blood smear examination showed no absolute and atypical lymphocytosis. Cytomegalovirus PCR in the blood and throat culture for streptococcus were negative. There was no splenomegaly. He was managed conservatively with intravenous fluids, bed rest, antipyretics and reduction of immunosuppression. Conclusions: EBV serological markers have a limited role in the early diagnosis of EBV-IM following RT in prior seronegative children. Initial heterophile antibody test may also be negative, and hence a repeat test may be necessary. Once becoming positive, the VCA IgM may remain persistently elevated for prolonged duration. In addition to the suppressed cellular immunity secondary to immunosuppression, humoral response to viral infections is also delayed in transplant recipients, especially in the early transplant period. Hence, routine monitoring with PCR is superior to serology in diagnosing IM early and monitoring the EBV infection post-RT for timely evaluation and management.\n\nEpstein–Barr virusserologymononucleosisrenal transplantpediatric\n==== Body\n1. Introduction\nEpstein–Barr virus (EBV), a double-stranded, enveloped DNA virus, belonging to the gamma herpes virus family, is the most common cause of infectious mononucleosis (IM). EBV infects over 90% of the human population worldwide and the rates of infection are higher among ages 15–24 years with 6–8 cases/1000 persons per year [1]. By four years of age, EBV seroprevalence is close to 100% in developing countries and 25–50% in lower socioeconomic groups in the United States [2]. IM is characterized by a triad of fever, tonsillar pharyngitis, and cervical lymphadenopathy [3]. The primary modes of exposure are saliva, organ transplantation or blood transfusion [4,5]. EBV-associated IM is a benign lymphoproliferative disorder in most immunocompetent patients, but may cause significant morbidity and mortality in those who are immunosuppressed, including renal transplant (RT) recipients [6,7]. EBV predominantly infects the epithelial and B cells. In RT recipients, the decreased anti-EBV T-cell immune surveillance, due to usage of immunosuppressive agents, may allow aberrant outgrowth of EBV-transformed B-cells leading to malignant post-transplant lymphoproliferative disorders (PTLD) [8,9,10]. The risk for developing PTLD is especially higher in pre-transplant EBV seronegative recipients, which is true for most young children. The incidence rate of PTLD is 4–22% for the various categories of pediatric organ transplant recipients as opposed to an average of 1–2% in adults [11].\n\nSimilar to the non-immunosuppressed patients, the presumptive diagnosis of EBV-associated IM in immunosuppressed RT recipients can be made clinically. However, a definite diagnosis does require demonstration of positive EBV serology and/or heterophile test since IM-like clinical picture can be seen with cytomegalovirus (CMV), human immunodeficiency virus (HIV) and Group A streptococcal infections [12,13], among others. The virus-specific serology poses a challenge, especially in prior seronegative children, due to delayed or absent humoral response [14]. In addition, heterophile tests (monospot) tests are less sensitive early in the course of illness and in young children [15,16]. Hence, relying on these tests only may cause a delay in diagnosis. Quantitative polymerase chain reaction (PCR) to detect EBV DNA in whole blood or serum is used to monitor EBV infection in the RT recipients [17]. Since PCR is independent of the body’s ability to mount cellular or humoral immunity, it can be a more reliable test to confirm EBV mononucleosis in the presence of clinical signs and symptoms. Here, we present a 14-year-old EBV-seronegative adolescent who presented with typical clinical features of IM, negative serology and monospot test, but with positive PCR, three months after RT from a seropositive donor.\n\n2. Methodology\nHeterophile antibody test was performed by both solid phase immunoassay and by latex agglutination assay. Antibodies to viral capsid antigen (VCA) IgM and IgG, early and nuclear antigens, were performed by semi-quantitative chemiluminescent immunoassay. EBV viral load was measured by quantitative PCR.\n\n3. Case Presentation\nA 14-year-old Caucasian male with hemophilia B underwent a deceased donor RT for end stage renal disease secondary to ischemic renal injury from intra-abdominal bleeding at birth. Chronic nightly peritoneal dialysis was initiated five months prior to the transplant. Treatment for hemophilia B included factor IX replacement therapy. He did not require blood transfusions due to the neonatal period. He had received all routine immunizations prior to the transplant. Induction was done with a total of 4.5 mg/kg of Thymoglobulin and maintenance immunosuppression consisted of tacrolimus and mycophenolate. He was on a steroid withdrawal protocol. There was an EBV mismatch between the donor and recipient (donor positive and recipient negative for EBV immunoglobulin (Ig) G). His serum EBV VCA IgG was 10.5 IU/mL (not detected: 17.9 U/mL or less) at the time of transplant. Both donor and recipient were CMV IgG positive. He had an immediate recovery of renal function post-RT with baseline serum creatinine of 0.9–1 mg/dL. Monthly viral surveillances for EBV, CMV and BK virus post-RT showed absence of viremia by PCR. Three months post–RT, he presented with fever, sore throat, and fatigue. His immunosuppression regimen at that time included tacrolimus 1.5 mg twice daily and mycophenolate 500 mg twice daily. Serum trough tacrolimus levels were at therapeutic level, as per our institution’s protocol. Anti-infective prophylaxis consisted of sulfamethoxazole-trimethoprim 800–160 mg three times weekly, and valganciclovir 450 mg daily. He had completed a 6-week course of prophylactic nystatin post-RT. Treatment of hemophilia B continued with once weekly factor IX infusions. There were no household sick contacts and he denied oral contact with another person. He had no other post-operative complications or acute rejection and reported adherence to the medications. \n\nTen days prior to this presentation, the patient had developed a sore throat and fatigue for a week. Both the rapid streptococcal and heterophile antibody test by latex agglutination were negative at that time. Supportive measures for viral pharyngitis were done; however, over the next 10 days, his symptoms progressed with the development of fever, prompting this presentation. \n\nOn examination, his vital signs were as follows: temperature 101.1 ⁰F, pulse 100 beats per minute, respiratory rate 18 per minute, oxygen saturation 99% on room air, and blood pressure 130/80 mm Hg. Height and weight were both at 50th centile. He was ill-appearing and was sitting in a tripod position. Throat and neck examination showed significant bilateral tonsillar enlargement, erythema, and exudate (Figure 1) and tender anterior cervical lymphadenopathy. Abdominal examination showed no tenderness to palpation over his transplanted kidney in his right lower quadrant and an absence of splenomegaly. Investigations revealed elevated serum C-reactive protein of 40 mg/L (0–5 mg/L), white blood cell count of 3.4 × 103/mm3, absolute neutrophil and lymphocyte count of 2800 cells/µL and 240 cells/µL, respectively, and atypical lymphocytes of 1%. Hemoglobin, platelet count and liver function test were all in normal range. Renal function test showed serum creatinine of 1.2 mg/dL (baseline 0.9–1 mg/dL) with stable electrolytes. Given EBV discordance (donor EBV + and recipient EBV −) along with fever, exudative tonsillitis, cervical lymphadenopathy and fever, there was a high index of suspicion for IM secondary to EBV. However, the heterophile antibody test by both solid phase immunoassay and latex agglutination assays was negative again. Furthermore, the serologic tests were all negative (EBV VCA IgM < 10 U/mL (not detected: 0–43.9 IU/mL), VCA IgG 15 IU/mL (not detected: 0–17.9 IU/mL), early antigen (EA) IgG < 5 IU/mL (not detected: 0–8.9 IU/mL), nuclear antigen (EBNA) IgG < 3 IU/mL (not detected: 0–17.9 IU/mL)). Serum CMV PCR and BK virus PCRs were negative. Whole blood EBV quantitative PCR showed EBV viral load of 1970 copies/mL. (undetectable: <390 copies/mL; ARUP laboratories, Salt lake City, UT, USA). Prior EBV PCR loads were undetectable at one and two month post-RT follow-up appointments. Bartonella henselae, Bartonella quintana, Toxoplasma gondii IgG and IgM antibodies along with serum adenovirus PCR were all negative. Serum tacrolimus trough level was at goal (6–7 ng/mL, as per our institution’s protocol). Hepatitis screen, HIV, antinuclear antibody, and rheumatoid factor were negative. Peripheral blood smear did not show evidence of blast cells. Abdominal sonogram showed normal appearing renal transplant with no splenomegaly. Throat culture was negative for beta-hemolytic streptococcus, corynebacterium diphtheriae, fungus, chlamydia and gonorrhea. Nasopharyngeal swab test for influenza and other respiratory viruses were negative. Due to tripod position on examination, X-ray along with computed tomography scan of the neck without contrast were done which showed narrowing of the airway due to soft tissue swelling but without any peritonsillar or retropharyngeal abscess. However, his respiratory status remained stable on room air throughout without the need for supplemental oxygen therapy. Steroid therapy was not required. He also developed acute hemoptysis, most likely secondary to tonsillar friability in the setting of low factor IX levels, prompting administration of an additional dose of factor IX with resolution of hemoptysis. He was treated with acetaminophen, intravenous fluid therapy and 3rd generation cephalosporin, the latter was discontinued after the throat and blood bacterial cultures resulted negative. Mycophenolate dose was decreased to 250 mg twice daily. He was discharged to home on sixth day of admission once he became afebrile and adequate oral intake was ensured. Discharge medications consisted of tacrolimus, mycophenolate, valganciclovir, TMP-SMX and factor IX replacement therapy. \n\nAt subsequent outpatient clinic follow-up visits, whole blood EBV PCR showed a persistent rise to a peak level of 10,200 copies/mL at 6 months, and then gradual decline to 2460 copies/mL at 9 months post-RT (Figure 2). VCA IgM and IgG both became positive at 5 months and subsequently peaked at his most recent 9-month follow-up (Figure 2). Monospot test (latex agglutination) also became positive at 5 months and remained positive at the 9 month post-RT follow-up. Clinical examination showed persistent mild sore throat, tonsillar enlargement and cervical lymphadenopathy until about 5 months when the symptoms started resolving. At his most recent 9-month follow-up visit, he was asymptomatic with resolution of tonsillar enlargement and cervical lymphadenopathy. Renal allograft function remained stable. Serum CMV and BK virus PCRs remained negative. \n\n4. Discussion\nEBV infection in transplant recipients may be a primary infection or a reactivation of a prior latent infection [8,18]. Primary infection occurs mainly via exchange of saliva or sharing household items from close-contacts, transplantation of kidney from a seropositive donor in a seronegative recipient or through blood transfusions [19,20]. Reactivation occurs in those with latent EBV and then undergo active viral multiplication in the setting of immunosuppression post–RT. The serologic diagnosis of reactivation/reinfection requires a 10-fold increase in anti-VCA IgG or the presence of anti-VCA IgM in previously IgG seropositive patients [21]. Our patient did not have a history of saliva exchange, sick contacts, and blood transfusions; hence he most likely had a primary infection through the transplantation from the seropositive donor. A single center study of pediatric solid organ transplant (SOT) recipients showed that the seroconversion rate in prior seronegative pediatric liver transplant patients was >75% while reactivation occurred in 50% of prior seropositive recipients [22]. Patients with primary infection had more viral shedding than those who were seropositive at the time of transplant, and heart transplant recipients had higher levels of peak shedding than renal allograft recipients [23]. In terms of risk factor for development of PTLD, primary EBV infection has been shown to be much more of a risk than reactivated infection [24]. Ho et al. described 11 children with EBV-associated lymphoproliferative syndrome post-SOT and 10 had a primary infection. These children were at greater risk due to them being seronegative for EBV prior to the transplant who then acquired primary infection with the transplant from seropositive donor [22]. Other studies have similarly shown that recipients who are seronegative at the time of transplant are more likely to be symptomatic and have EBV related complications, such as PTLD [6,7,25]. \n\nThe most commonly used tests to diagnose EBV-associated IM include heterophile test, serology and PCR. Paul–Bunnell test, the original heterophile antibody test, utilized sheep red blood cells (RBC) while most of the currently used heterophile antibody or the Monospot tests use horse RBCs with improvement in the test if these RBCs were first absorbed to guinea pig kidney or bovine RBCs before sera were added [26]. In immunocompetent patients, initially, the B cells produce polyclonal antibodies in response to EBV infection which are directed against viral and unrelated antigens found on sheep and horse RBCs. The antibodies against the latter antigens, termed heterophile antibodies, comprise only about 5% of total polyclonal antibodies [27]. They are mostly IgM antibodies that do not cross-react with EBV antigens and are the basis of heterophile antibody test [28,29]. Later in the course of EBV infection, these B cells are kept in check by the recruitment of cytotoxic CD8+ T cells which provide a polyclonal regulatory response, and are an important part of host defense mechanism against EBV [30]. Since the peak levels of virus-specific IgM and IgG response usually occurs only around 6–17 days after the onset of clinical symptoms, the serology may not be helpful in the early stage of presentation [31]. The incubation period of IM is usually 2–7 weeks and since the heterophile antibodies are seen 2–9 weeks after the person is infected, heterophile antibody tests may be preferable for early diagnosis at the time of presentation. Commercial test kits for these antibodies (by solid phase immunoassay or latex agglutination assay) are available and have sensitivities of 70–92% and a specificity of 96–100%, with a lower sensitivity in the first two weeks of illness [32]. The false negativity rate of these tests could be as high as 25% in the first week, 5–10% in the second week, and 5% in the third week [15]. Latex-based heterophile antibody assays may be a little more sensitive than the solid phase assays but the specificity is similar between the two [33]. Our patient was tested with both solid phase and latex agglutination assays. In addition, in younger patients less than 12 years of age, the test sensitivity is only 25–50%, as compared to 71–91% in older patients [15]. Horwitz et al. showed that children 1–2 years of age were significantly less likely to have positive heterophile antibody tests compared with children 2–4 years of age (27.3% vs. 76.2%) [16]. Therefore, heterophile tests may only be appropriate for use in older children. Once formed, these antibodies disappear in few weeks but in some, they may persist for up to a year after infection [28]. Hence, heterophile antibody tests may help diagnose IM retrospectively in some patients, if the initial test was negative, as in our case. Moreover, the antibodies detected by the test can be caused by conditions other than IM (for example, CMV, hepatitis, rubella, HIV, autoimmune conditions, adenovirus) due to cross reactivity with these conditions [32]. Our patient had negative CMV and adenovirus PCRs along with negative hepatitis and HIV tests. Due to these limitations, Center for Disease Control and Prevention in Unites States does not recommend the heterophile test for general use in the diagnosis of IM, instead suggesting viral serology as a method of choice [34]. \n\nThe initial serologic response to EBV infection occurs with the production of IgM antibody to the VCA in about 75% of patients [35], which usually disappears within 4–6 weeks. In immunosuppressed patients, however, the viral shedding may be prolonged, symptoms may last longer and be more severe [36]. Hence, once the intense immunosuppression period of T lymphocyte depletion is over (usually few months post-transplant), in the setting of persistent viral shedding, the newly produced host T cells will continue to stimulate B cells to produce virus-specific IgM and IgG. This could have led to the delayed onset but more prolonged presence of IgM antibody in our patient. Anti-VCA IgG also appears in the acute phase of EBV infection, peaks at 2–4 weeks after onset in most patients, declines slightly and then persists for the rest of a person’s life. Hence, the presence of VCA IgG indicates that the infection has occurred in the past. Antibody to early antigen (EA) is present in 60–80% only, and may indicate active viral replication and is especially helpful if the heterophile antibody is negative and VCA IgG or IgM yields inconclusive results. Of note, 20% of healthy individuals can have EBV EA antigen [35]. Anti-EA IgG generally falls to undetectable levels after 3–6 months. Antibody to nuclear antigen (EBNA) is not seen in the acute phase but slowly appears 2–4 months after the onset of symptoms and persists for the rest of a person’s life [37]. The infection then remains latent. Hence, the comparison of paired sera from acute and convalescent period showing presence of EBNA IgG in the absence of VCA IgM rules out the acute infection. With regards to the efficacy of serology, Bruu et al. analyzed six commercial tests for EBV-specific antibodies, with sensitivities ranging from 95–100% and specificities ranging from 86–100% [38]. Hence, EBV-specific serology appears to be more sensitive but less specific than heterophile antibody testing. The reduced specificity is due to significant cross-reactivity of VCA-IgM to other infections such as CMV [38]. On the other hand, increased sensitivity of serology, including IgM, can produce false positive results [39].\n\nSimilar to the delayed serological response after immunization in SOT recipients [40], serology unfortunately is unreliable as a diagnostic test for either PTLD or primary EBV infection in transplant recipients [8]. These patients show a marked delay in their humoral response to EBV antigens, and many fail to develop IgM antibodies altogether [8,14,41]. Both T and B cells are required to induce an antibody response. T follicular helper cells provide seven main forms of T cell help to B cells: signals that promote survival, proliferation, plasma cell differentiation, hypermutation, class-switch recombination, adhesion and chemo-attraction (cell migration) [42]. Hence, in the absence of cytotoxic T cells secondary to usage of lymphocyte-depleting immunosuppressive agents, the humoral response is also inhibited along with cellular immunity [42]. This state of T cell anergy allows EBV to escape the immune elimination by utilizing a distinct latency expression programs to establish a persistent infection and potentially leading to PTLD [30,43]. It is important to remember that T cell anergy can also occur due to T cell receptor-specific impairment in the induction of genes involved in T cell proliferation, allowing uninhibited proliferation of infected B cells, in some immunocompetent patients with acute IM [44]. Regardless of the mechanism of anergy, the antibody response is reduced and in some cases may be selective. Diminished or absent antibody response to EBNA may be observed despite persistence of anti VCA IgG. Cen et al. described a markedly reduced antibody response to the latent cycle antigens, EBNA 1, EBNA 2 and EBNA-LP in immunosuppressed SOT recipients with PTLD, but not to the lytic cycle VCA when compared to the normal immunocompetent controls [45]. At 9-month follow-up, our patient had not been able to produce anti-EBNA IgG although the VCA IgG had reached its peak level. Hence, the typical pattern of appearance of serological markers may not be evident in these patients. \n\nEBV PCR measures the quantitative viral load in the blood and is the most sensitive test for detecting EBV infection in the post-transplant period [17]. A variety of blood specimens have been used for EBV load quantification, including unfractionated whole blood, peripheral blood mononuclear cells, and plasma. However, the whole blood EBV DNA is believed to be superior to plasma EBV DNA as the cell-associated EBV can be detected well before the plasma DNA is detected. Additionally, the cell DNA may be present at high levels without even being present in the plasma [21,46]. The whole blood sample is also simple to process and provides quantification of both cell-associated and cell-free virus, yielding an absolute viral load, irrespective of concerns about fluctuations in cell number, lysis and loss during separation [17]. Hence, transplant clinical guidelines suggest monitoring of high-risk patients for EBV-related PTLD by nucleic acid testing post-RT instead of serology [47]. In a large, retrospective study of the incidence of PTLD in RT recipients in the United States, the risk of PTLD was more than six times higher for donor+/recipient- deceased donor transplants compared with R+ transplants [48]. However, there are no clinical guidelines that exist for diagnosis of EBV-IM without PTLD in the post-RT period. Since the EBV serology and heterophile tests may be negative in the early post-RT period, this report emphasizes the value of repeat testing of serology and heterophile tests to establish a diagnosis of IM. It is important to know that since low level detection of EBV by PCR is common in transplant recipients [49], the mere presence of a positive viral load does not always indicate mononucleosis in the absence of the classic presentation such as lymphadenopathy, pharyngitis and fever. Hence, the serial testing of serology and heterophile tests may have a role in retrospectively establishing a diagnosis of IM in these patients. \n\nOther tests that may be useful in diagnosis of IM are lymphocyte to white cell count ratio, real-time PCR targeting various EBV genes, an absolute increase in the number of peripheral lymphocytes, and atypical lymphocytes [50,51,52]. Studies on lymphocyte to white cell count ratio as a diagnostic marker of IM has shown conflicting results [50]. Usage of raised absolute lymphocyte count has been suggested as providing a quick clue to the diagnosis of IM while awaiting for serology or heterophile antibody test result [52]. The atypical lymphocytes are primary T cells, produced in response to the EBV-infected B cells [29]. Commonly, absolute lymphocytosis (>50% lymphocytes) in the presence of >10% atypical lymphocytes are considered diagnostic of IM. The case presented in this report did not have absolute lymphocytosis with only 1% atypical lymphocytes, most likely secondary to lymphopenia from immunosuppression. Hence, lymphocyte-based assays are unlikely to be useful in transplant recipients, especially in the early post-transplant period. \n\n5. Conclusions\nThe EBV serology may underestimate the active presence of EBV in seronegative SOT recipients. Furthermore, in the absence of positive heterophile antibodies, the confirmatory diagnosis of mononucleosis becomes much more difficult. Not only has the EBV DNA load in the blood allowed risk assessment of development of EBV-associated disease in immunosuppressed patients, it also is helpful in making a definite diagnosis of IM in the presence of clinical signs and symptoms.\n\nAuthor Contributions\nA.B.: Collected data and prepared the original draft; R.B., F.J.: Collected data and prepared the original draft, and critically reviewed and revised the manuscript. K.U.: Conceptualized the study, collected data and prepared the original draft, and critically reviewed and revised the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis study received no funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Oropharyngeal examination showing bilateral tonsillar enlargement with exudates.\n\nFigure 2 Timeline of Epstein–Barr virus (EBV) serology and polymerase chain reaction (PCR) post-renal transplantation. EBV serologies (viral capsid antigen (VCA) IgM, VCA IgG, early antigen (EA) and nuclear antigen (EBNA) IgG expressed in IU/mL) and EBV DNA PCR expressed in copies/mL.\n==== Refs\nReferences\n1. Fleisher G. Henle W. Henle G. Lennette E.T. Biggar R.J. Primary infection with Epstein-Barr virus in infants in the United States J. Infect. Dis. 1979 139 553 558 10.1093/infdis/139.5.553 220340 \n2. Gares V. Panico L. Castagne R. Delpierre C. Kelly-Irving M. 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Otolaryngol. 2011 36 515 516 10.1111/j.1749-4486.2011.02367.x 22032455\n\n", "fulltext_license": "CC BY", "issn_linking": "2305-6320", "issue": "7(4)", "journal": "Medicines (Basel, Switzerland)", "keywords": "Epstein–Barr virus; mononucleosis; pediatric; renal transplant; serology", "medline_ta": "Medicines (Basel)", "mesh_terms": null, "nlm_unique_id": "101671069", "other_id": null, "pages": null, "pmc": null, "pmid": "32331303", "pubdate": "2020-04-22", "publication_types": "D002363:Case Reports", "references": "9077426;25774295;23042966;18159378;18094380;1628427;6260269;10589949;25677493;29202893;27193039;4158937;8167350;1328412;4316146;30656214;11283064;2995512;8382973;1670959;3146367;28130396;19013244;6199144;7804700;10655355;220340;22032455;2828417;15508538;8555507;20860842;15541197;27500242;27016725;21108750;12153173;226884;5697368;1320711;23451126;19845597;14523386;25013625;23717200;10799460;11283029;10944566;2833828;22273720", "title": "Limited Utility of Serology and Heterophile Test in the Early Diagnosis of Epstein-Barr Virus Mononucleosis in a Child after Renal Transplantation.", "title_normalized": "limited utility of serology and heterophile test in the early diagnosis of epstein barr virus mononucleosis in a child after renal transplantation" }

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{ "abstract": "To investigate the efficacy of intravitreal injection of recombinant tissue plasminogen activator (rt-PA), ranibizumab, and gas without vitrectomy for submacular hemorrhage.\n\n\n\nProspective, interventional, consecutive case series.\n\n\n\nTwenty consecutive patients (20 eyes) with submacular hemorrhage secondary to exudative age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV).\n\n\n\nRanibizumab, rt-PA (25 μg/0.05 ml), and 100% perfluoropropane (0.3 ml) were injected intravitreally, followed by 2-day prone positioning.\n\n\n\nThe primary outcome measure was best-corrected visual acuity (BCVA) 6 months after treatment. Secondary outcome measures included central retinal thickness (CRT), central pigment epithelial detachment (PED) thickness, central ellipsoid zone, recurrence rate, and complications.\n\n\n\nUnderlying disease was exudative AMD in 1 eye and PCV in 19 eyes. Submacular hemorrhage ranged in size from 2 to 31 disc diameters. Complete displacement of submacular hemorrhage was achieved in 17 eyes (85%), and partial displacement was achieved in 3 eyes (15%). Snellen BCVA improved from 20/139 before treatment to 20/65 at 6 months (P = 0.0061). Mean change in Early Treatment Diabetic Retinopathy Study score from baseline was +13 letters (P = 0.0040). Mean CRT decreased from 599 μm before treatment to 208 μm at 6 months (P < 0.0001), and central PED thickness decreased from 188 to 88 μm (P = 0.0140). Three eyes developed vitreous hemorrhage, and 1 eye developed retinal detachment; all were treated surgically, and Snellen BCVA improved at 6 months (P = 0.0012). Recurrence was observed in 10 eyes (50%) within 6 months, but visual acuity was preserved with intravitreal injection of anti-vascular endothelial growth factor (VEGF) pro re nata (PRN). The factors that affect BCVA at 6 months after treatment were pre- and posttreatment central ellipsoid zone (P = 0.0366 and P = 0.0424), pretreatment BCVA (P = 0.0015), and pre- and posttreatment central PED thickness (P = 0.0046, P = 0.0021).\n\n\n\nSubretinal hemorrhage treatment by intravitreal injection of rt-PA, ranibizumab, and gas is useful to achieve hemorrhage displacement and lesion improvement. To preserve visual acuity, early detection of posttreatment recurrence and intravitreal anti-VEGF injection PRN are necessary.", "affiliations": "Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan. Electronic address: [email protected].;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.;Department of Ophthalmology, School of Medicine, Nihon University, Kanda, Chiyodaku, Tokyo, Japan.", "authors": "Kitagawa|Yorihisa|Y|;Shimada|Hiroyuki|H|;Mori|Ryusaburo|R|;Tanaka|Kouji|K|;Yuzawa|Mitsuko|M|", "chemical_list": "D020533:Angiogenesis Inhibitors; D005343:Fibrinolytic Agents; D005466:Fluorocarbons; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C042852:perflutren; D010959:Tissue Plasminogen Activator; D000069579:Ranibizumab", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0161-6420", "issue": "123(6)", "journal": "Ophthalmology", "keywords": null, "medline_ta": "Ophthalmology", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D020256:Choroidal Neovascularization; D003131:Combined Modality Therapy; D058450:Endotamponade; D005260:Female; D005343:Fibrinolytic Agents; D005451:Fluorescein Angiography; D005466:Fluorocarbons; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D011127:Polyps; D016684:Prone Position; D011446:Prospective Studies; D000069579:Ranibizumab; D012166:Retinal Hemorrhage; D010959:Tissue Plasminogen Activator; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration", "nlm_unique_id": "7802443", "other_id": null, "pages": "1278-86", "pmc": null, "pmid": "26949121", "pubdate": "2016-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Intravitreal Tissue Plasminogen Activator, Ranibizumab, and Gas Injection for Submacular Hemorrhage in Polypoidal Choroidal Vasculopathy.", "title_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy" }

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INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR, RANIBIZUMAB, AND GAS INJECTION FOR SUBMACULAR HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. OPHTHALMOLOGY 2015 NOV 06;:1-9.", "literaturereference_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160405", "receivedate": "20160405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12237598, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-ROCHE-1737204", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, 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"patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitreous haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITAGAWA Y, SHIMADA H, MORI R, TANAKA K AND YUZUWA T. INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR, RANIBIZUMAB, AND GAS INJECTION FOR SUBMACULAR HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. OPHTHALMOLOGY 2015 NOV 06;:1-9.", "literaturereference_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160405", "receivedate": "20160405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12237578, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-ROCHE-1737207", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PERFLUTREN" }, 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"patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitreous haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KITAGAWA Y, SHIMADA H, MORI R, TANAKA K AND YUZUWA T. INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR, RANIBIZUMAB, AND GAS INJECTION FOR SUBMACULAR HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. OPHTHALMOLOGY 2015 NOV 06;:1-9.", "literaturereference_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160406", "receivedate": "20160406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12240690, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-ROCHE-1733784", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, 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INTRAVITREAL TISSUE PLASMINOGEN ACTIVATOR, RANIBIZUMAB, AND GAS INJECTION FOR SUBMACULAR HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. OPHTHALMOLOGY 2015 NOV 06;:1-9.", "literaturereference_normalized": "intravitreal tissue plasminogen activator ranibizumab and gas injection for submacular hemorrhage in polypoidal choroidal vasculopathy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160405", "receivedate": "20160405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12237643, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "OBJECTIVE\nThe objective of this study was to characterize chemotherapy treatment patterns in elderly patients with epithelial ovarian cancer (EOC) and their impact on overall survival (OS).\n\n\nMETHODS\nWe identified patients age ≥65years with stage II-IV EOC who underwent cytoreduction from 2003 to 2011. Relevant clinical variables were extracted and correlated with OS. Statistical analyses were performed using logistic regression, Kaplan-Meier methods, and multivariable Cox proportional hazard models.\n\n\nRESULTS\nOne hundred and eighty-four patients were included in the analysis. The average age was 73years with American Society of Anesthesiology Physical Status Class 2 or 3. Approximately 78% underwent primary debulking surgery (PDS). OS for the entire cohort was 3.3years. One hundred and fifty-seven patients received adjuvant chemotherapy, of which 70% received initial platinum-based doublet therapy; 67.5% of patients were able to complete the intended six cycles of chemotherapy; of these, 34% experienced a dose reduction and 45% experienced one or more dose delays. Any dose delay was associated with a decrease in overall survival (p=0.02) and remained significant even after controlling for age, stage, and residual disease and number of chemotherapy cycles received (p=0.029).\n\n\nCONCLUSIONS\nElderly EOC patients frequently required chemotherapy dose reductions and delays in chemotherapy administration. Multivariate analysis confirmed that dose delays are an independent factor associated with decreased OS.", "affiliations": "Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].;Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Founders 5 Suite 546A, Boston, MA 02115, USA. Electronic address: [email protected].", "authors": "Joseph|Naima|N|;Clark|Rachel M|RM|;Dizon|Don S|DS|;Lee|Malinda S|MS|;Goodman|Annekathryn|A|;Boruta|David|D|;Schorge|John O|JO|;Del Carmen|Marcela G|MG|;Growdon|Whitfield B|WB|", "chemical_list": "D009944:Organoplatinum Compounds", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0090-8258", "issue": "137(3)", "journal": "Gynecologic oncology", "keywords": "Chemotherapy; Dose delay; Elderly; Ovarian cancer", "medline_ta": "Gynecol Oncol", "mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial; D009503:Neutropenia; D009944:Organoplatinum Compounds; D010051:Ovarian Neoplasms; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015996:Survival Rate; D061665:Time-to-Treatment", "nlm_unique_id": "0365304", "other_id": null, "pages": "401-5", "pmc": null, "pmid": "25839911", "pubdate": "2015-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer.", "title_normalized": "delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer" }

[ { "companynumb": "US-ROCHE-1775520", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN EPITHELIAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN EPITHELIAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN EPITHELIAL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal obstruction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure congestive", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Influenza", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device related infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diverticulitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myocardial infarction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cellulitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Clostridium difficile infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Embolism venous", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOSEPH J, CLARK R, DIZON D, LEE M, GOODMAN A, BORUTA D, SCHORGE J AND DEL CARMEN M AND GROWDON W. DELAY IN CHEMOTHERAPY ADMINISTRATION IMPACTS SURVIVAL IN ELDERLY PATIENTS WITH EPITHELIAL OVARIAN CANCER.. GYNECOLOGIC ONCOLOGY 2015;137(3):401-405.", "literaturereference_normalized": "delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160615", "receivedate": "20160615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12470016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "Congenital sideroblastic anemia (CSA) is a rare hereditary disease causing disorders of hemoglobin synthesis. Severe, progressive congenital sideroblastic anemia becomes transfusion dependent and results in iron overload. In such cases, patients must undergo stem cell transplantation (SCT) before critical organ dysfunction occurs. However, there has been no consensus on the criteria for SCT for congenital sideroblastic anemia. A 17-year-old Japanese boy was newly diagnosed with congenital sideroblastic anemia manifesting dyspnea on effort. His gene analysis revealed ALAS2 R170L. He gradually become dependent on RBC transfusion. Vitamin B6 (pyridoxal, 30 mg/day) therapy and high-dose alpha-linoleic acid supplementation (150 mg/day) had not been effective. We treated the patient with reduced-intensity SCT from a human leukocyte antigen (HLA) alle 8/8-identical unrelated female donor. The preparation regimen applied consisted of cyclophosphamide, fludarabine, total body irradiation (2 Gy), and anti-thymocyte globulin. We experienced secondary graft failure, nevertheless we used enough immunosuppression. Here we discuss the optimal transplantation regimen for an adult-onset congenital sideroblastic anemia patient with transfusion dependency and mild hemosiderosis. We consider a positive indication for SCT in younger (< 20-year-old) patients with congenital sideroblastic anemia with transfusion dependency. Each case should be individually considered for their suitability for SCT depending on the feasibility and the clinical condition of the patient.", "affiliations": "a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.;a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.;a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.;a Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Kagawa University , Kagawa , Japan.", "authors": "Imataki|Osamu|O|;Uchida|Shumpei|S|;Uemura|Makiko|M|;Kadowaki|Norimitsu|N|", "chemical_list": "D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human", "country": "England", "delete": false, "doi": "10.1080/08880018.2019.1578844", "fulltext": null, "fulltext_license": null, "issn_linking": "0888-0018", "issue": "36(1)", "journal": "Pediatric hematology and oncology", "keywords": null, "medline_ta": "Pediatr Hematol Oncol", "mesh_terms": "D000624:5-Aminolevulinate Synthetase; D000293:Adolescent; D064591:Allografts; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic; D006084:Graft Rejection; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D033581:Stem Cell Transplantation", "nlm_unique_id": "8700164", "other_id": null, "pages": "46-51", "pmc": null, "pmid": "30912988", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Graft failure after reduced-intensity stem cell transplantation for congenital sideroblastic anemia.", "title_normalized": "graft failure after reduced intensity stem cell transplantation for congenital sideroblastic anemia" }

[ { "companynumb": "JP-MYLANLABS-2019M1049010", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF PREPARATIVE REGIMEN: ON DAYS -6 TO -3", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FROM DAY 25 TO DAY 41; LATER THE DOSE WAS TAPERED", "drugenddate": null, "drugenddateformat": null, "drugindication": "STEROID THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.03 MILLIGRAM/KILOGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".03", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF PREPARATIVE REGIMEN: ON DAYS -6 TO-3", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LATER ADJUSTED TO 12-15 NG/ML BY THERAPEUTIC DOSE MONITORING", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF PREPARATIVE REGIMEN: ON DAY -1", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTI-THYMOCYTE-GLOBULIN; RABBIT" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IMATAKI O, UCHIDA S, UEMURA M, KADOWAKI N. GRAFT FAILURE AFTER REDUCED-INTENSITY STEM CELL TRANSPLANTATION FOR CONGENITAL SIDEROBLASTIC ANEMIA. PEDIATR-HEMATOL-ONCOL 2019?36(1):46-51.. 2019?36(1):46-51", "literaturereference_normalized": "graft failure after reduced intensity stem cell transplantation for congenital sideroblastic anemia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190524", "receivedate": "20190524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16353458, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "JP-TEVA-2019-JP-1058510", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 3 AND DAY 6", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FROM DAY 25 TO DAY 41, LATER THE DOSE WAS TAPERED", "drugenddate": null, "drugenddateformat": null, "drugindication": "STEROID THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".03", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF PREPARATIVE REGIMEN: ON DAY -1", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTI-THYMOCYTE-GLOBULIN (RABBIT)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LATER ADJUSTED TO 12-15 NG/ML BY THERAPEUTIC DOSE MONITORING", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF PREPARATIVE REGIMEN: ON DAYS -6 TO-3", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PART OF PREPARATIVE REGIMEN: ON DAYS -6 TO -3", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IMATAKI O, UCHIDA S, UEMURA M, KADOWAKI N. GRAFT FAILURE AFTER REDUCED-INTENSITY STEM CELL TRANSPLANTATION FOR CONGENITAL SIDEROBLASTIC ANEMIA. PEDIATR-HEMATOL-ONCOL 2019?36(1):46-51.", "literaturereference_normalized": "graft failure after reduced intensity stem cell transplantation for congenital sideroblastic anemia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190605", "receivedate": "20190605", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16393089, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-209822", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLY ADMINISTERED AT 0.03MG/KG AND ADJUSTED TO 12-15 NG/ML BY THERAPEUTIC DOSE MONITORING", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, DAILY; FROM DAY 25 TO DAY 41", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENGRAFTMENT SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10, 7, AND 7MG/M2 ON DAYS 1, 3, AND 6, RESPECTIVELY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MILLIGRAM/SQ. METER FOR FOUR DAYS; DAYS -6 TO -3),", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM/SQ. METER FOR FOUR DAYS; DAYS -6 TO -3", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "IMATAKI O, UCHIDA S, UEMURA M, KADOWAKI N. GRAFT FAILURE AFTER REDUCED-INTENSITY STEM CELL TRANSPLANTATION FOR CONGENITAL SIDEROBLASTIC ANEMIA. PEDIATR HEMATOL ONCOL. 2019?23-JAN? 36(1):46-51", "literaturereference_normalized": "graft failure after reduced intensity stem cell transplantation for congenital sideroblastic anemia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190606", "receivedate": "20190606", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16396982, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "We report a case of junctional rhythm that occurred both preoperatively and later during a portion of general anesthesia. A 19-year-old woman was scheduled to undergo bilateral sagittal split ramus osteotomy after being diagnosed with a jaw deformity. Preoperative electrocardiography (ECG) revealed a junctional rhythm with a slow heart rate (HR). At 90 minutes after anesthesia induction, local anesthesia with 10 mL of 1% lidocaine and 1:100,000 adrenaline was administered. A junctional rhythm appeared 15 minutes after the local anesthesia. We believe that the atrioventricular nodal pacemaker cells accelerated because of the increased sympathetic activity due to the adrenaline. On the preoperative ECG, the junctional rhythm with slow HR appeared as an escaped beat caused by slowing of the primary pacemaker. Therefore, we think that the preoperative junctional rhythm and the junctional rhythm that appeared during general anesthesia were due to different causes. Understanding the cause of a junctional rhythm could lead to more appropriate treatment. We therefore believe that identifying the cause of the junctional rhythm is important in anesthetic management.", "affiliations": "Department of Anesthesiology, Osaka Dental University, Osaka, Japan.;Department of Anesthesiology, Osaka Dental University, Osaka, Japan.;Department of Anesthesiology, Osaka Dental University, Osaka, Japan.", "authors": "Kishimoto|Naotaka|N|;Kinoshita|Ikue|I|;Momota|Yoshihiro|Y|", "chemical_list": "D008012:Lidocaine; D004837:Epinephrine", "country": "United States", "delete": false, "doi": "10.2344/anpr-64-03-08", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-3006", "issue": "64(3)", "journal": "Anesthesia progress", "keywords": "Adrenaline; Arrhythmia; Atrioventricular node; General anesthesia; Junctional rhythm", "medline_ta": "Anesth Prog", "mesh_terms": "D000768:Anesthesia, General; D001145:Arrhythmias, Cardiac; D001919:Bradycardia; D004562:Electrocardiography; D004837:Epinephrine; D005260:Female; D006801:Humans; D008012:Lidocaine; D019647:Oral Surgical Procedures; D057234:Preoperative Period; D055815:Young Adult", "nlm_unique_id": "0043533", "other_id": null, "pages": "165-167", "pmc": null, "pmid": "28858547", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "5044017;15242446;17180134;6336804;16548866;19243330;3970369", "title": "Junctional Rhythm Preoperatively and During General Anesthesia for Oral and Maxillofacial Surgery.", "title_normalized": "junctional rhythm preoperatively and during general anesthesia for oral and maxillofacial surgery" }

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INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMIFENTANIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPINEPHRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019430", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1:100000 ; 10 ML (LIDOCAINE ALONG WITH EPINEPHRINE)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPINEPHRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ROCURONIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROCURONIUM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4.5?5.0 MICROG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MICROG", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MICROG/ML ; PROPOFOL INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "REMIFENTANIL" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MICROG/KG/MIN; INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMIFENTANIL" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "50", "reaction": [ { "reactionmeddrapt": "Nodal rhythm", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KISHIMOTO N, KINOSHITA I, MOMOTA Y. JUNCTIONAL RHYTHM PREOPERATIVELY AND DURING GENERAL ANESTHESIA FOR ORAL AND MAXILLOFACIAL SURGERY. ANESTH?PROG 2017?64(3):165?167.", "literaturereference_normalized": "junctional rhythm preoperatively and during general anesthesia for oral and maxillofacial surgery", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180706", "receivedate": "20180706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15117410, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "This study evaluates the frequency and causes of dolutegravir (DTG) discontinuation along 5 years of follow-up, in both antiretroviral treatment (ART)-naive and experienced people living with HIV (PLWH). This is a prospective multi-center cohort study enrolling PLWH on DTG from July 2014 until November 2020. DTG-durability was investigated using the Kaplan-Meier survival curve. The Cox proportional-hazards model was used for estimating the hazard ratio (HR) of DTG discontinuation for any cause, and for adverse events (AEs). Nine hundred sixty-three PLWH were included, 25.3% were women and 28.0% were ART-naive. Discontinuations for any causes were 10.1 [95% confidence interval (95% CI) 8.9-11.5] per 100 person-years, similar in most regimens, with the apparent exception of tenofovir alafenamide/emtricitabine+DTG (p < 0.0001). In the multivariable Cox regression model, non-Caucasian ethnicity, age ≥50 years, and lower estimated glomerular filtration rate (eGFR) were associated with a higher probability of DTG interruption. The incidence rate of virological failure was 0.4 (95% CI 0.2-0.7) per 100 person-years, while the estimated discontinuation rate for AEs was 4.0 (3.2-4.9) per 100 person-years. Thirty-four DTG interruptions were due to grade ≥3 events (10 central nervous system, 6 hypersensitivity, 3 renal, 3 myalgia/asthenia, 3 abdominal pain, 2 gastrointestinal, and 7 other events). People with lower body mass index, age ≥50 years, and lower eGFR were at higher risk of AEs, while dual combinations were protective (HR 0.41 compared with abacavir/lamivudine/DTG, 95% CI 0.22-0.77). In this prospective observational study, we found high DTG durability and a low rate of virological failures. Dual therapies seemed protective toward AEs and might be considered, when feasible, a suitable option to minimize drug interactions and improve tolerability.", "affiliations": "Infectious Disease Clinic, IRCCS Policlinico San Martino Hospital, Genoa, Italy.;Unit of Infectious and Tropical Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.;Fondazione ASIA Onlus, Buccinasco, Italy.;Unit of Infectious Diseases, \"Divisione A\", Amedeo di Savoia Hospital, Torino, Italy.;Infectious Diseases Clinic, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.;Unit of Infectious Diseases, ASST della Valle Olona, Busto Arsizio Hospital, Busto Arsizio, Italy.;Infectious Disease Unit, Ospedale A. Manzoni, Lecco, Italy.;Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.;Clinic of Infectious Diseases, Department of Medicine 2, Azienda Ospedaliera di Perugia, Santa Maria Hospital, Perugia, Italy.;Unit of Infectious Diseases, Department of Human Pathology of the Adult and the Developmental Age 'G. Barresi', University of Messina, Messina, Italy.;Infectious Diseases Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.;Unit of Infectious Diseases, University of Catania, ARNAS Garibaldi, Catania, Italy.;Department of Medical and Surgical Sciences, Clinics of Infectious Diseases, S. Orsola-Malpighi Hospital, \"Alma Mater Studiorum\" University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Biomedical and Clinical Sciences 'Luigi Sacco', Università degli Studi di Milano, Milan, Italy.;Infectious Disease Unit (I Divisione), ASST Fatebenefratelli Sacco, Milan, Italy.;SOD Malattie Infettive e Tropicali AOU Careggi, Florence, Italy.;Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.;Department of Infectious Disease, University of Campania Luigi Vanvitelli, Naples, Italy.;Infectious Diseases Department, SOC 1, USLCENTROFIRENZE, Santa Maria Annunziata Hospital, Florence, Italy.;Infectious Diseases Unit, SS Trinità Hospital, Cagliari, Italy.;Department of Infectious and Tropical Diseases, St. Annunziata Hospital, Cosenza, Italy.;Infectious Diseases Department, Sanremo Hospital, Sanremo, Italy.;Infectious Disease Clinic, IRCCS Policlinico San Martino Hospital, Genoa, Italy.;Infectious Disease Unit, Department of Internal Medicine, Fondazione IRCCS Ca' Granda, University of Milan, Ospedale Maggiore Policlinico, Milan, Italy.;Clinic of Infectious Diseases, Department of Medicine and Science of Aging, University 'G. d'Annunzio' Chieti-Pescara, Chieti, Italy.;Infectious Diseases Clinic, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.;Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, San Martino Hospital-IRCCS, Genoa, Italy.;Unit of Infectious and Tropical Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.", "authors": "Taramasso|Lucia|L|0000-0002-6622-6358;De Vito|Andrea|A|;Ricci|Elena Delfina|ED|;Orofino|Giancarlo|G|;Squillace|Nicola|N|;Menzaghi|Barbara|B|;Molteni|Chiara|C|;Gulminetti|Roberto|R|;De Socio|Giuseppe Vittorio|GV|;Pellicanò|Giovanni Francesco|GF|;Sarchi|Eleonora|E|;Celesia|Benedetto Maurizio|BM|;Calza|Leonardo|L|;Rusconi|Stefano|S|;Valsecchi|Laura|L|;Martinelli|Canio Vito|CV|;Cascio|Antonio|A|;Maggi|Paolo|P|;Vichi|Francesca|F|;Angioni|Goffredo|G|;Guadagnino|Giuliana|G|;Cenderello|Giovanni|G|;Dentone|Chiara|C|;Bandera|Alessandra|A|;Falasca|Katia|K|;Bonfanti|Paolo|P|;Di Biagio|Antonio|A|;Madeddu|Giordano|G|;|||", "chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir", "country": "United States", "delete": false, "doi": "10.1089/apc.2021.0089", "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2914", "issue": "35(9)", "journal": "AIDS patient care and STDs", "keywords": "HIV; adverse events; dolutegravir; durability; safety; toxicity; virolgical failure", "medline_ta": "AIDS Patient Care STDS", "mesh_terms": "D019380:Anti-HIV Agents; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011446:Prospective Studies; D011728:Pyridones", "nlm_unique_id": "9607225", "other_id": null, "pages": "342-353", "pmc": null, "pmid": "34524918", "pubdate": "2021-09", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Durability of Dolutegravir-Based Regimens: A 5-Year Prospective Observational Study.", "title_normalized": "durability of dolutegravir based regimens a 5 year prospective observational study" }

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{ "abstract": "Current lymphogranuloma venereum (LGV) guidelines mainly focus on anorectal infections. Inguinal LGV infections have been rare in the current epidemic among men who have sex with men (MSM), but might require a different approach not yet recommended in current guidelines for the treatment and diagnosis of LGV. We describe 4 inguinal LGV cases. Three MSM developed inguinal LGV infection several weeks after a previous consultation, of which two had received azithromycin after being notified for LGV. Three failed the recommended 21 days doxycycline treatment. These inguinal LGV cases highlight 3 pitfalls in the current standard management of LGV: (1) Urethral chlamydia infections in MSM can be caused by LGV biovars that in contrast to non-LGV biovars require prolonged antibiotic therapy. (2) The recommended one gram azithromycin contact treatment seems insufficient to prevent established infections. (3) Inguinal LGV may require prolonged courses of doxycycline, exceeding the currently advised 21 days regimen.", "affiliations": "Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands.;General Practitioners Office Heijnen & de Meij, Amsterdam, The Netherlands.;Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands The Netherlands STI Outpatient Clinic, Public Health Service Amsterdam, Amsterdam, The Netherlands Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.", "authors": "Oud|Emerentiana Veronica|EV|;de Vrieze|Nynke Hesselina Neeltje|NH|;de Meij|Arjan|A|;de Vries|Henry John C|HJ|", "chemical_list": "D000900:Anti-Bacterial Agents; D017963:Azithromycin; D004318:Doxycycline", "country": "England", "delete": false, "doi": "10.1136/sextrans-2013-051427", "fulltext": null, "fulltext_license": null, "issn_linking": "1368-4973", "issue": "90(4)", "journal": "Sexually transmitted infections", "keywords": "Human immunodeficiency virus; Lymphogranuloma venereum; Men who have sex with men; Sexually transmitted infection", "medline_ta": "Sex Transm Infect", "mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002690:Chlamydia Infections; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline; D015658:HIV Infections; D006526:Hepatitis C; D018451:Homosexuality, Male; D006801:Humans; D007264:Inguinal Canal; D008219:Lymphogranuloma Venereum; D008297:Male; D008875:Middle Aged; D017211:Treatment Failure; D014522:Urethral Diseases", "nlm_unique_id": "9805554", "other_id": null, "pages": "279-82", "pmc": null, "pmid": "24787368", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum: important lessons from a case series.", "title_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series" }

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PITFALLS IN THE DIAGNOSIS AND MANAGEMENT OF INGUINAL LYMPHOGRANULOMA VENEREUM: IMPORTANT LESSONS FROM A CASE SERIES. 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PITFALLS IN THE DIAGNOSIS AND MANAGEMENT OF INGUINAL LYMPHOGRANULOMA VENEREUM: IMPORTANT LESSONS FROM A CASE SERIES. SEX TRANSM INFECT. 2014;90(4):279-82", "literaturereference_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20140729", "receivedate": "20140729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10348050, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "NL-ACTAVIS-2014-16208", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065041", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "100 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "LYMPHOGRANULOMA VENEREUM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE MONOHYDRATE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug effect delayed", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OUD EV, DE VRIEZE NH, DE MEIJ A, DE VRIES HJ. PITFALLS IN THE DIAGNOSIS AND MANAGEMENT OF INGUINAL LYMPHOGRANULOMA VENEREUM: IMPORTANT LESSONS FROM A CASE SERIES. SEX TRANSM INFECT. 2014;90(4):279-82", "literaturereference_normalized": "pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum important lessons from a case series", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20140729", "receivedate": "20140729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10348053, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib.\n\n\n\nThis phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib.\n\n\n\nWhen a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed.\n\n\n\nThe addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers.\n\n\n\nClinicalTrials.gov identifier, NCT02804399.", "affiliations": "Global Product Development, Pfizer Oncology, New York, NY, USA. [email protected].;Global Product Development, Clinical Pharmacology, Pfizer Oncology, La Jolla, CA, USA.;Global Product Development, Pfizer Inc., New Haven, CT, USA.;Global Product Development, Pfizer Oncology, New York, NY, USA.;Safety Surveillance and Risk Management, Pfizer Oncology, Groton, CT, USA.;Global Product Development, Pfizer Inc., Groton, CT, USA.;Global Product Development, Pfizer Inc., South Lyon, MI, USA.;Global Product Development, Pfizer Inc., Groton, CT, USA.;Global Product Development, Clinical Pharmacology, Pfizer Oncology, La Jolla, CA, USA.", "authors": "Chen|Joseph|J|http://orcid.org/0000-0002-5998-7765;Xu|Huiping|H|;Pawlak|Sylvester|S|;James|Leonard P|LP|;Peltz|Gerson|G|;Lee|Kimberly|K|;Ginman|Katherine|K|;Bergeron|Michelle|M|;Pithavala|Yazdi K|YK|", "chemical_list": "D000631:Aminopyridines; D000970:Antineoplastic Agents; D007769:Lactams; D047029:Lactams, Macrocyclic; D011720:Pyrazoles; C000590786:lorlatinib; D012293:Rifampin", "country": "United States", "delete": false, "doi": "10.1007/s12325-019-01198-9", "fulltext": null, "fulltext_license": null, "issn_linking": "0741-238X", "issue": "37(2)", "journal": "Advances in therapy", "keywords": "Drug–drug interaction; Healthy participants; Lorlatinib; Pharmacokinetics; Rifampin; Safety", "medline_ta": "Adv Ther", "mesh_terms": "D000328:Adult; D000631:Aminopyridines; D000970:Antineoplastic Agents; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D012293:Rifampin; D055815:Young Adult", "nlm_unique_id": "8611864", "other_id": null, "pages": "745-758", "pmc": null, "pmid": "31863284", "pubdate": "2020-02", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.", "title_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants" }

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THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665174, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037008", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "600 MILLIGRAM(2 CAPSULES OF 300MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. 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THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665267, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037006", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED ...", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665176, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037012", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100MG (ADMINISTERED..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037005", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE...", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665186, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037014", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE WITH..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17669606, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037283", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665262, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037000", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE SWALLOWED WHOLE WITH APPROXIMATELY 240ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665172, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037203", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17666160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037004", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR 25MG TABLETS THAT WERE TO BE..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200415", "receivedate": "20200415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17669605, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "US-MYLANLABS-2020M1037002", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "2 CAPSULES OF 300MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LORLATINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100MG (ADMINISTERED AS FOUR..", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORLATINIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHEN J, XU H, PAWLAK S, JAMES LP, PELTZ G, LEE K, ET AL. THE EFFECT OF RIFAMPIN ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB: RESULTS OF A PHASE ONE, OPEN-LABEL, CROSSOVER STUDY IN HEALTHY PARTICIPANTS. ADV-THER 2020?37(2):745-758.", "literaturereference_normalized": "the effect of rifampin on the pharmacokinetics and safety of lorlatinib results of a phase one open label crossover study in healthy participants", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200414", "receivedate": "20200414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17665175, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]

{ "abstract": "A 6 month-old-female infant from Bahrain visiting Germany with her family for a holiday was seen by us for extensive dermatophytosis of the back, buttocks, chest and groins. Topical treatment by terbinafine for over 2 months was not successful. Other family members including adults and children were treated in Bahrain with topical antifungals and oral voriconazole which was not helpful. Mycological examination performed in Germany revealed the detection of the zoophilic dermatophyte Trichophyton (T.) mentagrophytes. The newly described genotype VIII within the species T. mentagrophytes was identified by sequencing of the \"internal transcribed spacer\" (ITS) region of the fungal rDNA. This genotype of T. mentagrophytes is the main causative agent of the current epidemic of chronic recalcitrant dermatophytoses in India. Transmission of this Indian genotype of T. mentagrophytes to other countries due to globalization is a serious issue to be considered. Moreover, a significant percentage of these Indian T. mentagrophytes strains are resistant to terbinafine both in vitro and by the way of genetic point mutations in the squalene epoxidase (SQLE) gene. Some are also found to be partially resistant against itraconazole and voriconazole. The point mutation TTC/TTA was found by SQLE mutation analysis in this particular T. mentagrophyte isolate from Bahrain. This point mutation is closely associated with F397L amino acid substitution of the enzyme indicative of in vitro resistance of the dermatophyte against terbinafine. The girl was successfully treated by topical miconazole and later by ciclopirox olamine. This is the first report on an infection due to a terbinafine-resistant T. mentagrophytes strain of the ITS genotype VIII from India in Germany.", "affiliations": "Hautärztin, Gemeinschaftspraxis Allgemeinmedizin und Dermatologie, Kurfürstenstr. 23a, 54616, Wittlich, Deutschland.;Labor für Medizinische Mikrobiologie, Mölbiser Hauptstr. 8, 04571, Rötha OT Mölbis, Deutschland.;Allgemeinmedizinische Praxis Dr. med. Alfons Ludes und Thorsten Koech, Poststr, 5, 54340, Leiwen, Deutschland.;\"Nirvan\" and \"In Skin\" Clinics, Vadodara, Gujarat, Indien.;Dermatology Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Schweiz.;Labor für Medizinische Mikrobiologie, Mölbiser Hauptstr. 8, 04571, Rötha OT Mölbis, Deutschland.;Labor für Medizinische Mikrobiologie, Mölbiser Hauptstr. 8, 04571, Rötha OT Mölbis, Deutschland. [email protected].", "authors": "Süß|Anke|A|;Uhrlaß|Silke|S|;Ludes|Alfons|A|;Verma|Shyam B|SB|;Monod|Michel|M|;Krüger|Constanze|C|;Nenoff|Pietro|P|", "chemical_list": "D000935:Antifungal Agents; D012331:RNA, Fungal; D000077768:Ciclopirox; D008825:Miconazole; D000077291:Terbinafine", "country": "Germany", "delete": false, "doi": "10.1007/s00105-019-4431-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0017-8470", "issue": "70(11)", "journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete", "keywords": "Ciclopirox olamine; Dermatomycoses; Miconazole; Mutation analysis; Point mutation", "medline_ta": "Hautarzt", "mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001445:Bahrain; D000077768:Ciclopirox; D005260:Female; D005838:Genotype; D005858:Germany; D006801:Humans; D007223:Infant; D008825:Miconazole; D012331:RNA, Fungal; D017423:Sequence Analysis, RNA; D000077291:Terbinafine; D014005:Tinea; D014006:Tinea Capitis; D014249:Trichophyton", "nlm_unique_id": "0372755", "other_id": null, "pages": "888-896", "pmc": null, "pmid": "31098692", "pubdate": "2019-11", "publication_types": "D016428:Journal Article", "references": "30284315;27783317;29722887;30187579;29577447;30507401;30275090;28416557;27071492;29512606;29893296;29485088;30561859;26886443;28584364;29706004;22587730;29976522;23532505", "title": "Extensive tinea corporis due to a terbinafine-resistant Trichophyton mentagrophytes isolate of the Indian genotype in a young infant from Bahrain in Germany.", "title_normalized": "extensive tinea corporis due to a terbinafine resistant trichophyton mentagrophytes isolate of the indian genotype in a young infant from bahrain in germany" }

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{ "abstract": "Human T-lymphotropic virus type I (HTLV-I) is a retrovirus associated with adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In addition to HAM/TSP and ATL, HTLV-I-associated encephalopathy and cerebellar involvement have been reported. We report a case of an 87-year-old Japanese woman presenting with progressive dysarthria and gait disturbance. Neurological examination showed word-finding difficulty, scanning speech, saccadic eye movements, ocular dysmetria, gaze-evoked nystagmus and bilateral dysmetria. There was no motor weakness or spasticity. HTLV-I antibody was detected in both her serum and cerebrospinal fluid. Cerebrospinal fluid neopterin (57 pg/mL) and IgG index (3.27) were significantly elevated. MRI showed cerebellar swelling. She was finally diagnosed with HTLV-I associated cerebellitis. Two courses of high-dose intravenous methylpredonine therapy attenuated cerebellar ataxia and cerebellar swelling. It suggests that cerebellitis can result from HTLV-I infection, regardless of the existence of ATL or HAM/TSP.", "affiliations": "Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan [email protected].;Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.;Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.;Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.", "authors": "Mizuma|Atsushi|A|;Enokida|Kumiko|K|;Nagata|Eiichiro|E|;Takizawa|Shunya|S|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2020-241366", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(6)", "journal": "BMJ case reports", "keywords": "brain stem / cerebellum; infection (neurology)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D002524:Cerebellar Ataxia; D005260:Female; D015490:HTLV-I Infections; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D009759:Nystagmus, Pathologic; D015493:Paraparesis, Tropical Spastic", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "34099448", "pubdate": "2021-06-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cerebellitis in a human T-lymphotropic virus type 1 carrier: a case report.", "title_normalized": "cerebellitis in a human t lymphotropic virus type 1 carrier a case report" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Interleukin-2 receptor increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adult T-cell lymphoma/leukaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIZUMA A, ENOKIDA K, NAGATA E, TAKIZAWA S. 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{ "abstract": "Non-vitamin K oral anticoagulants (NOACs) are being increasingly prescribed. These drugs act rapidly, have predictable dose-related anticoagulation effect and require no routine laboratory monitoring, making them attractive for both patients and healthcare providers. All NOACs are at least partially excreted thought the kidneys. Renal injury related to NOAC use is being increasingly reported. NOAC-related acute interstitial nephritis (AIN) has only been reported once and that was in context of dabigatran use. We describe the first case of apixaban-related AIN. This case adds an important differential diagnoses that should be considered for any patient presenting with renal injury while being treated with NOACs.", "affiliations": "Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.", "authors": "Abdulhadi|Basma|B|http://orcid.org/0000-0003-2359-6612;Mulki|Ramzi|R|;Goyal|Abhinav|A|;Rangaswami|Janani|J|", "chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-221641", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "acute renal failure; drugs and medicines; renal system", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D003937:Diagnosis, Differential; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D009395:Nephritis, Interstitial; D011720:Pyrazoles; D011728:Pyridones", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28847995", "pubdate": "2017-08-28", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12825841;18832478;24859719;26144101;26347498;26670286;26698882;26885473;4176988", "title": "Novel oral anticoagulant and kidney injury: apixaban-related acute interstitial nephritis.", "title_normalized": "novel oral anticoagulant and kidney injury apixaban related acute interstitial nephritis" }

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{ "abstract": "This is a report on two cases of refractory schizophrenia and two cases of clozapine-resistant schizophrenia successful treated with paliperidone palmitate. To the authors' knowledge, this is the first report of the successful use of paliperidone palmitate in such patients.", "affiliations": "From the Hospital das Clínicas, Monte Alegre, Ribeirão Preto, São Paulo, Brazil; the University of São Paulo; the Dept. of Psychiatry, Federal University of São Paulo; and the Dept. of Neuroscience and Behavior, School of Medicine of Ribeirão Preto, São Paulo, Brazil.", "authors": "Maia-de-Oliveira|João Paulo|JP|;Nunes|Emerson Arcoverde|EA|;Ushirohira|Juliana Mayumi|JM|;Machado-de-Sousa|João Paulo|JP|;Bressan|Rodrigo Affosenca|RA|;Hallak|Jaime Eduardo Cecílio|JE|", "chemical_list": "D014150:Antipsychotic Agents; D007555:Isoxazoles; D010168:Palmitates; D003024:Clozapine; D000068882:Paliperidone Palmitate", "country": "United States", "delete": false, "doi": "10.1176/appi.neuropsych.13120374", "fulltext": null, "fulltext_license": null, "issn_linking": "0895-0172", "issue": "27(1)", "journal": "The Journal of neuropsychiatry and clinical neurosciences", "keywords": null, "medline_ta": "J Neuropsychiatry Clin Neurosci", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D005260:Female; D006801:Humans; D007555:Isoxazoles; D008297:Male; D000068882:Paliperidone Palmitate; D010168:Palmitates; D012559:Schizophrenia; D055815:Young Adult", "nlm_unique_id": "8911344", "other_id": null, "pages": "e14-6", "pmc": null, "pmid": "25716490", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Paliperidone palmitate for refractory and clozapine-resistant schizophrenia.", "title_normalized": "paliperidone palmitate for refractory and clozapine resistant schizophrenia" }

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{ "abstract": "BACKGROUND\nAssociation of leukoencephalopathy and atypical mycobacteriosis has been rarely reported. We present a case that is relevant for its unusual presentation and because it may shed further light on the pathogenic mechanisms underlying reversible encephalopathies.\n\n\nMETHODS\nWe report the case of a Hispanic 64-year-old woman with cognitive decline and extensive leukoencephalopathy. Magnetic resonance imaging revealed white-matter lesions with increased water diffusivity, without blood-brain-barrier disruption. Brain biopsy showed tissue rarefaction with vacuolation, mild inflammation, few reactive astrocytes and decreased aquaporin water-channel expression in the lesions. Six months later, she was diagnosed with atypical mycobacterial pulmonary infection. Brain lesions resolved after antimycobacterial treatment.\n\n\nCONCLUSIONS\nWe hypothesize leukoencephalopathic changes and vasogenic edema were associated with decreased aquaporin expression. Further studies should clarify if reversible leukoencephalopathy has a causal relationship with decreased aquaporin expression and atypical mycobacterial infection, and mechanisms underlying leukoencephalopathy resolution after antimycobacterial treatment. This article may contribute to the understanding of pathogenic mechanisms underlying magnetic resonance imaging subcortical lesions and edema, which remain incompletely understood.", "affiliations": "Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Departments of Neurology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Institute of Radiology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Department of Pathology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].;Multiple Sclerosis Therapeutics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. [email protected].;Multiple Sclerosis Therapeutics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. [email protected].;Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900, São Paulo, SP, Brazil. [email protected].", "authors": "Oliveira|Marcos C B|MC|;Sato|Douglas Kazutoshi|DK|;Soares-Neto|Herval R|HR|;Lucato|Leandro T|LT|;Callegaro|Dagoberto|D|;Nitrini|Ricardo|R|;Medeiros|Raphael S S|RS|;Misu|Tatsuro|T|;Fujihara|Kazuo|K|;Castro|Luiz H|LH|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "England", "delete": false, "doi": "10.1186/s12883-015-0415-0", "fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 41510.1186/s12883-015-0415-0Case ReportLeukoencephalopathy resolution after atypical mycobacterial treatment: a case report Oliveira Marcos C. B. [email protected] Sato Douglas Kazutoshi [email protected] Soares-Neto Herval R. [email protected] Lucato Leandro T. [email protected] Callegaro Dagoberto [email protected] Nitrini Ricardo [email protected] Medeiros Raphael S. S. [email protected] Misu Tatsuro [email protected] Fujihara Kazuo [email protected] Castro Luiz H. [email protected] Department of Neurology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900 São Paulo, SP Brazil Institute of Radiology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900 São Paulo, SP Brazil Department of Pathology, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 5o andar, sala 5011, 05403-900 São Paulo, SP Brazil Departments of Neurology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan Multiple Sclerosis Therapeutics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan 2 9 2015 2 9 2015 2015 15 15925 3 2015 25 8 2015 © Oliveira et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAssociation of leukoencephalopathy and atypical mycobacteriosis has been rarely reported. We present a case that is relevant for its unusual presentation and because it may shed further light on the pathogenic mechanisms underlying reversible encephalopathies.\n\nCase report\nWe report the case of a Hispanic 64-year-old woman with cognitive decline and extensive leukoencephalopathy. Magnetic resonance imaging revealed white-matter lesions with increased water diffusivity, without blood–brain-barrier disruption. Brain biopsy showed tissue rarefaction with vacuolation, mild inflammation, few reactive astrocytes and decreased aquaporin water-channel expression in the lesions. Six months later, she was diagnosed with atypical mycobacterial pulmonary infection. Brain lesions resolved after antimycobacterial treatment.\n\nConclusion\nWe hypothesize leukoencephalopathic changes and vasogenic edema were associated with decreased aquaporin expression. Further studies should clarify if reversible leukoencephalopathy has a causal relationship with decreased aquaporin expression and atypical mycobacterial infection, and mechanisms underlying leukoencephalopathy resolution after antimycobacterial treatment. This article may contribute to the understanding of pathogenic mechanisms underlying magnetic resonance imaging subcortical lesions and edema, which remain incompletely understood.\n\nKeywords\nReversible encephalopathy syndromePRESMycobacteriosisLeukoencephalopathyVasogenic edemaAquaporin water-channelissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nReversible leukoencephalopathy is characterized by headaches, seizures, vomiting, and confusion, associated with extensive bilateral white-matter subcortical neuroimaging abnormalities, suggestive of vasogenic edema without infarction [1]. Most cases of reversible encephalopathy are referred to as posterior reversible encephalopathy syndrome (PRES), since white matter changes are more prominent in the posterior cerebral regions. Brainstem, cerebellum and other brain regions may also be affected [2]. PRES has been associated with severe hypertension (including eclampsia), renal dysfunction, infection, autoimune disease, and immunosuppressant drug use [1–7]. The hallmark of PRES is reversible cerebral edema due to blood–brain-barrier dysfunction [8]. Pathogenic mechanisms underlying magnetic resonance imaging (MRI) subcortical lesions and edema remains incompletely understood.\n\nAssociation of brain edema and mycobacteria has previously been reported in the setting of Mycobacterium tuberculosis infection [9–15], and in one patient who presented with acute disseminated encephalomyelitis (ADEM) associated with Mycobacterium intracellulare meningitis, who responded to high dose steroid pulse therapy [16]. In all reported cases of mycobacterial infection associated with edema, underlying mechanisms involved demyelination and inflammation. Association of a non-demyelinating leukoencephalopathy and atypical mycobacteriosis has not, to our knowledge, been previously reported.\n\nWe report neuroimaging and brain histology features of a patient with extensive leukoencephalopathy with brain edema and absence of demyelination, that resolved after atypical mycobacterial pulmonary infection treatment.\n\nCase presentation\nA Hispanic 64-year-old woman was admitted with headaches, vomiting and confusion. A month earlier, the patient presented with subacute new-onset headaches, nausea, vomiting, gait impairment, and anorexia. There was no history of fever, cough, abdominal pain, previous medical disease or immunosuppressant drug use. Blood pressure was normal. Physical examination was unremarkable. Neurologic examination showed an unsteady gait, without motor weakness or ataxia. Cognitive tests showed a Mini-Mental Status Exam (MMSE) score of 18/30, impaired attention, executive functions, verbal fluency and episodic memory (Table 1).Table 1 Cognitive evaluations in a patient with reversible leukoencephalopathy before and after atypical mycobacteria treatment\n\n\tInitial assessment\tFive months after initial assessment (no mycobacterial treatment)\tEighteen months after initial assessment (one year of mycobaterial treatment)\t\nMini Mental State Exam (MMSE)\t18/30\t18/30\t22/30\t\nDigit span (direct/indirect)\t3 / 0\t3 / 0\t4 / 2\t\nShort Memory Test with 10 items (incidental memory / immediate memory / learning)*\n\t3 / 7 / 8\t4 / 1 / 1\t5 / 7 / 8\t\nDelayed Memory Test with 10 items (after distraction) without / with hints*\n\t6 (1) / 8\t3 / 4 (3)\t8 / 10\t\nVerbal fluency (semantic / phonemic)\t5 (animals) / 1 (letter P)\t6 (animals) / 1 (letter P)\t10 (animals) / 1 (letter P)\t\nClock-drawing test\tDisexecutive: distortion of number placement (4 points)\tDisexecutive: crowding numbers to one side (5 points)\tMore noticeable errors in hand/number placement (8 points)\t\nFunctional Activity Questionnaire (FAQ)\t\t25/30\t10/30\t\nPatient’s education: 4 Years\n\nLegend: *Number of intrusions between brackets\n\n\n\nBrain MRI disclosed diffuse and symmetric confluent nonenhancing white matter lesions, that were hyperintense in T2/FLAIR images (Fig. 1a to d). Corresponding apparent diffusion coefficients (ADC) maps suggested vasogenic edema (Fig. 1f). MRI angiography was unremarkable (not shown). Multivoxel spectroscopy, dynamic susceptibility contrast (DSC) perfusion (T2*) and dynamic contrast-enhanced (DCE) permeability (T1) did not disclose relevant abnormalities (Fig. 1e, g and h). Cerebrospinal fluid analysis showed a normal cell count (4 cells/mm3), protein (32 mg/dL) and glucose (80 mg/dL) levels, normal protein electrophoresis values, negative oligoclonal bands and polymerase chain reaction for infectious agents (including tuberculosis). Systemic evaluation was negative for cancer, autoimmune diseases (Anti-nuclear antibodies = negative, Anti-neutrophil cytoplasmic antibodies = negative), and infectious diseases. Thoracic computed tomography (CT) showed nonspecific patchy lung infiltrates. Blood laboratory tests were normal (i.e. Erythrocyte sedimentation rate = 2 mm; C-reactive protein = 1,3 mg/L; Leucocytes = 6,880/mm3). Electroencephalogram EEG showed mild diffuse slowing and brief bursts of diffuse delta waves. The patient underwent two brain biopsies that showed tissue rarefaction with vacuolation, very mild inflammatory cell and macrophage infiltrates, absence of demyelination, malignant cells or granulomas, and no signs of tissue infarction or hemorrhagic changes (Fig. 2a to j). Immunostaining showed scarce CD45+ lymphocytes and CD68+ macrophages, without axonal or myelin damage, with few reactive astrocytes and low aquaporin-4 staining in the lesion compared to the normal surrounding areas. Aquaporin-1 staining was also reduced in the lesion, less extensively than aquaporin-4.Fig. 1 Serial brain magnetic resonance imaging studies of a patient with reversible leukoencephalopathy. Brain magnetic resonance imaging (MRI). Initial FLAIR images (a-d) show diffuse symmetrical confluent hyperintensities involving cerebral white matter, extending to the brainstem and cerebellar white matter. Note mass effect evidenced by sulci, fissure and ventricle effacement (more remarkable considering patient’s age - 64 years old). Corresponding white matter MR spectroscopy (e) (multivoxel, TE = 135 ms) demonstrates no definite metabolic changes. Apparent diffusion coefficients (ADC) map (f) demonstrates diffusion facilitation, signaling vasogenic edema. There was no contrast enhancement (not shown) or significant changes appreciated in color maps proportional to relative cerebral blood volume (rCBV) (g) obtained from a dynamic susceptibility contrast (DSC) perfusion (T2*) study. Color maps proportional to wash in rate (h) obtained from a dynamic contrast-enhanced (DCE) permeability (T1) sequence were also unremarkable. Images F-H are in the same level as D. After treatment for atypical mycobacteriosis, white matter changes disappeared, as shown in (FLAIR) images (i-l) obtained two years after the initial exam (arrows in J and L point to biopsy sites, partially characterized in these images)\n\nFig. 2 Brain biopsy results of a patient with reversible leukoencephalopathy. a to j: Brain biopsy results of the patient with reversible leukoencephalopathy prior to atypical mycobacteria treatment shows (a) mild tissue rarefaction with vacuolation, very sparse perivascular inflammatory infiltrates, and (b) no evidence of demyelination. c–d Presence of relatively few glial fibrillary acidic protein (GFAP) positive astrocytes with reduced aquaporin-4 expression in the lesion compared to the surrounding area. Scale bar = 100 μm. High magnification (400x) on D shows aquaporin-4 on the membrane of reactive astrocytes. Scale bar = 10 μm. e Aquaporin-1 expression is also reduced in the lesion, but in less extensively than aquaporin-4. f–g Myelin sheath is preserved with no loss of myelin basic protein (MBP) and myelin associated glycoprotein (MAG). h No signs of neuronal or axonal damage. i–j Few lymphocytes (CD45+) and macrophages (CD68+) are found in the perivascular space, while immunoglobulin and complement C9neo deposition are absent (not shown). Scale bar = 50 μm. (Magnification a–d = 100x; e–j = 200x)\n\n\n\nThe patient was treated initially with intravenous methylprednisolone (1 g/day for three days), followed by oral dexamethasone (10 mg/day) for six months. Clinical and neurologic status and brain MRI remained unchanged. Activities of daily living were impaired, with a Functional Activity Questionnaire (FAQ) score of 25 and MMSE score of 18. Whole body positron emission tomography-computed tomography obtained at this point revealed a hypermetabolic right pulmonary mass. Lesion histology showed granulomas containing Mycobacterium abscessus. The patient was treated with levofloxacin, clarithromycin and amycacin. Steroids were tapered and discontinued. A year later, cognitive functions and functional status were improved (MMSE = 21; FAQ score = 10) (Table 1), and brain MRI disclosed remarkable resolution of white matter changes (Fig. 1i–l).\n\nConclusions\nThis report illustrates a case of leukoencephalopathy associated with atypical pulmonary mycobacteriosis. Although we cannot establish a cause-effect relationship of atypical mycobacteriosis and leukoencephalopathy, lack of central nervous system (CNS) granulomas and caseous necrosis, lack neurological worsening following steroid therapy, and improvement after antimycobacterial treatment suggest a remote effect of the lung infection, causing the CNS disorder.\n\nInitial chest CT had initially shown nonspecific patchy lung infiltrates, that could, retrospectively, indicate early stage atypical mycobacterial infection. Additionally, the patient presented remarkable, albeit partial, neurological improvement after antimycobacterial treatment. There was no response to steroid therapy, brain pathology studies did not disclose inflammatory activity, and there was absence of intra-thecal antibody production, rendering the possibility of an adaptative immune mechanism (i.e. antibody or cell-mediated immune responses) extremely unlikely. Steroid therapy may have contributed to worsening of the mycobacterial lung infection.\n\nMycobacteria are known to be highly immunogenic: mycobacteria containing compounds are used in mouse models of ADEM and Multiple Sclerosis, through activation of adaptative immunity [17, 18]. Mycobacteria also activate the innate immune system, with production of cytokines and inflammation mediators, such as nitric oxide [19].\n\nMechanism of brain involvement in this case can be inferred from imaging and pathology findings of tissue edema with scarce reactive astrocytes, and reduced aquaporin-4 and aquaporin-1 expression in the lesion, compared to surrounding areas. Considering the lack of evidence of adaptative immune response in the brain, we speculate that activation of an innate-immune response in the lung either by the mycobacteria or through a host mediated response may have exerted a remote effect on aquaporin expression in the brain, leading to interstitial white matter edema. Alternatively, but less likely, antimycobacterial agents may have exerted a direct action reverting white matter lesions [20].\n\nFew studies have evaluated pathological findings in reversible encephalopathies [1, 2, 8, 21], and some studies suggest the pathogenic role of cellular channel dysfunction. Reversible leukoencephalopathy has been described in few anti-aquaporin-4 antibody positive neuromyelitis optica (NMO) cases following immunotherapeutic interventions [3]. Lesion reversibility in these cases suggests that immune-mediated tissue destruction associated with blood–brain barrier (BBB) disruption may not be the main underlying mechanism.\n\nIt is conceivable that vasogenic edema noted on diffusion-weighted MRI sequences in reversible leukoencephalopathy cases represents parenchymal excess water content, caused by impaired water influx control, independent from BBB disruption. In our case, water influx control was probably impaired due to astrocyte aquaporin dysfunction, in a mechanism akin to that hypothesized in brain edema associated with NMO [3]. Additionally, experimentally induced acute hypertension in rabbits led to exogenous markers leakage in arterioles and capillaries through channels (often sigmoid-shaped) and cytoplasm and by transendothelial pinocytosis, causing brain-barrier disruption and edema [22]. These findings suggest impaired water channel function as a possible mechanism underlying reversible leukoencephalopathy.\n\nWe are not aware of previous non-demyelinating reversible leukoencephalopathy cases that improved after atypical mycobacteriosis treatment. We found vacuolated white matter lesions with paucity of reactive astrogliosis and decreased aquaporin water-channel expression. A causal relationship between mycobacteriosis and interstitial edema remains speculative. Alternatively, unexpected drug effects may have contributed to brain changes resolution. Elucidating pathogenic mechanisms underlying reversible leukoencephalopathies may lead to improved therapeutic strategies to treat this condition.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nADEMAcute disseminated encephalomyelitis\n\nADCApparent diffusion coefficients\n\nBBBBlood–brain barrier\n\nCNSCentral nervous system\n\nCTComputed tomography\n\nDCEDynamic contrast-enhanced\n\nDSCDynamic susceptibility contrast\n\nFLAIRFluid attenuation inversion recovery\n\nFAQFunctional Activity Questionnaire\n\nMRIMagnetic resonance imaging\n\nMMSEMini-Mental Status Exam\n\nNMONeuromyelitis optica\n\nPRESPosterior reversible encephalopathy syndrome\n\nrCBVRelative cerebral blood volume\n\nCompeting interests\n\n\nDr. Oliveira has no conflicts of interest to disclose. Dr. Castro has no conflicts of interest to disclose. Dr. Sato is an associated editor of the Arquivos de Neuropsiquiatria (official journal of the Brazilian Academy of Neurology), receives scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, has received research support from Ichiro Kanehara Foundation (2011), and speaker honorarium from Novartis. Dr. Soares-Neto has no conflicts of interest to disclose. Dr. Lucato has no conflicts of interest to disclose. Dr. Callegaro has no conflicts of interest to disclose. Dr. Medeiros has no conflicts of interest to disclose. Prof. Misu has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. Prof. Fujihara serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and a advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010–2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present). Prof. Nitrini has no conflicts of interest to disclose.\n\nAuthors’ contributions\n\nMCBO = conception and study design, data analysis and drafting the manuscript; LHMC = study design, data analysis, and drafting the manuscript; DKS = study conception, data analysis and drafting the manuscript; HRSN = data analysis, and drafting the manuscript; LTL = data analysis and review of the manuscript; DC = conception of the study, data analysis and review of the manuscript; RSSM = data analysis and review of the manuscript; TM = design of the study, data analysis, and drafting the manuscript; KF = study conception, data analysis and review of the manuscript; RN = study conception, data analysis and review of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was partially supported by KAKENHI (22229008) of The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and by the Health and Labor Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labor and Welfare of Japan. The funding sources had no role in the design, collection, analysis, or interpretation of the study, nor in the writing of the article or decision to submit.\n==== Refs\nReferences\n1. Hinchey J Chaves C Appignani B Breen J Pao L Wang A A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 10.1056/NEJM199602223340803 8559202 \n2. Lee VH Wijdicks EM Manno EM Rabinstein AA Clinical spectrum of reversible posterior leukoencephalopathy syndrome Arch Neurol 2008 65 205 210 18268188 \n3. Magaña SM Matiello M Pittock SJ McKeon A Lennon VA Rabinstein AA Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders Neurology 2009 72 8 712 717 10.1212/01.wnl.0000343001.36493.ae 19237699 \n4. Mak A Chan BP Yeh IB Ho RC Boey ML Feng PH Neuropsychiatric lupus and reversible posterior leucoencephalopathy syndrome: a challenging clinical dilemma Rheumatology 2008 47 256 262 10.1093/rheumatology/kem319 18084001 \n5. Bartynski WS Boardman JF Zeigler ZR Shadduck RK Lister J Posterior reversible encephalopathy syndrome in infection, sepsis, and shock AJNR Am J Neuroradiol 2006 27 2179 2190 17110690 \n6. Guerriero S, Ciraci L, Centoducati T, Pignatelli F, Lamargese V, Salvati A, et al. Bilateral Visual Loss as Presenting Symptom of Posterior Reversible Encephalopathy Syndrome in a Patient with HIV/Tuberculosis Coinfection: A Case Report. Case Rep Ophthalmol Med. 2012; doi: 10.1155/2012/850176\n7. Viehman JA Khalil D Barhoma C Hanna RM Mycobacterium avium-intracellulare otomastoiditis in a young AIDS patient: case report and review of the literature Hiv/Aids 2013 5 61 66 23459156 \n8. Feske SK Posterior reversible encephalopathy syndrome: a review Semin Neurol 2011 31 202 215 10.1055/s-0031-1277990 21590625 \n9. Dastur DK Udani PM The pathology and pathogenesis of tuberculous encephalopathy Acta Neuropathol 1966 6 311 326 10.1007/BF00688161 5297864 \n10. Dastur DK The pathology and pathogenesis of tuberculous encephalopathy and myeloradiculopathy: a comparison with allergic encephalomyelitis Childs Nerv Syst 1986 2 13 19 10.1007/BF00274027 3731158 \n11. Udani PM Dastur DK Tuberculous encephalopathy with and without meningitis. Clinical features and pathological correlations J Neurol Sci 1970 10 541 561 10.1016/0022-510X(70)90187-5 5422557 \n12. Lammie GA Hewlett RH Schoeman JF Donald PR Tuberculous encephalopathy: a reappraisal Acta Neuropathol 2007 113 3 227 34 10.1007/s00401-006-0172-7 17171342 \n13. Kim HJ Shim KW Lee MK Park MS Kim SH Kim EY Tuberculous encephalopathy without meningitis: pathology and brain MRI findings Eur Neurol 2011 65 3 156 9 10.1159/000324170 21372574 \n14. Char G Morgan OS Tuberculous encephalopathy. A rare complication of pulmonary tuberculosis West Indian Med J 2000 49 1 70 2 10786460 \n15. Chetty KG Kim RC Mahutte CK Acute hemorrhagic leukoencephalitis during treatment for disseminated tuberculosis in a patient with AIDS Int J Tuberc Lung Dis 1997 1 6 579 81 9487459 \n16. Okada H Yoshioka K Acute Disseminated Encephalomyelitis Associated with Meningitis due to Mycobacterium intracellulare Inter Med 2010 49 2113 2116 10.2169/internalmedicine.49.3323 \n17. Wolf NA Amouzegar TK Swanborg RH Synergistic interaction between Toll-like receptor agonists is required for induction of experimental autoimmune encephalomyelitis in Lewis rats J Neuroimmunol 2007 185 1–2 115 22 10.1016/j.jneuroim.2007.02.001 17341432 \n18. Zorzella-Pezavento SF Guerino CP Chiuso-Minicucci F França TG Ishikawa LL Masson AP BCG and BCG/DNAhsp65 Vaccinations Promote Protective Effects without Deleterious Consequences for Experimental Autoimmune Encephalomyelitis Clin Dev Immunol 2013 2013 721383 10.1155/2013/721383 24288555 \n19. Lee J Sandor M Heninger E Fabry Z Mycobacteria-induced suppression of autoimmunity in the central nervous system J Neuroimmune Pharmacol 2010 5 2 210 9 10.1007/s11481-010-9199-6 20333556 \n20. Dalhoff A Shalit I Immunomodulatory effects of quinolones Lancet Infect Dis 2003 3 359 371 10.1016/S1473-3099(03)00658-3 12781508 \n21. Chester EM Agamanolis DP Banker BQ Victor M Hypertensive encephalopathy: a clinicopathologic study of 20 cases Neurology 1978 28 928 939 10.1212/WNL.28.9.928 567764 \n22. Hansson HA Johansson B Blomstrand C Ultrastructural studies on cerebrovascular permeability in acute hypertension Acta Neuropathol 1975 32 187 198 10.1007/BF00696568 1180001\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "15()", "journal": "BMC neurology", "keywords": null, "medline_ta": "BMC Neurol", "mesh_terms": "D000900:Anti-Bacterial Agents; D003072:Cognition Disorders; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies; D008171:Lung Diseases; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D066127:White Matter", "nlm_unique_id": "100968555", "other_id": null, "pages": "159", "pmc": null, "pmid": "26329680", "pubdate": "2015-09-02", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "23243537;24288555;21590625;5422557;17171342;20930438;12781508;19237699;567764;5297864;1180001;9487459;23459156;10786460;17110690;18084001;3731158;21372574;18268188;20333556;8559202;17341432", "title": "Leukoencephalopathy resolution after atypical mycobacterial treatment: a case report.", "title_normalized": "leukoencephalopathy resolution after atypical mycobacterial treatment a case report" }

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{ "abstract": "We report here 2 pediatric cases of multidrug-resistant (MDR) tuberculosis (TB) that were observed in Italy. Both families came from an Eastern European country, which is notably an area with a high prevalence of MDR TB. An increase of new cases of MDR TB in developed countries is expected over the next years because of migratory flow, and specific measures and strategies need to be taken to prevent the propagation and dissemination of MDR TB. An efficacious treatment including linezolid and moxifloxacin was administered for 13 months in 1 case. No adverse reactions were detected during close child monitoring. Linezolid and newer fluoroquinolones such as moxifloxacin have been reported to be effective for MDR-TB treatment in adults. On the contrary, there is limited available evidence regarding the effectiveness and safety of these drugs in infants and children with MDR TB. The use of second-line drugs not approved for use in children may be necessary to treat a life-threatening disease such as MDR TB, but it requires careful monitoring to quickly recognize the occurrence of dose- and duration-dependent adverse drug reactions.", "affiliations": "Clinic of Infectious Diseases, Department of Pediatrics, University of Turin, Regina Margherita Children's Hospital, Turin, Italy. [email protected]", "authors": "Pinon|Michele|M|;Scolfaro|Carlo|C|;Bignamini|Elisabetta|E|;Cordola|Giorgio|G|;Esposito|Irene|I|;Milano|Rosangela|R|;Mignone|Federica|F|;Bertaina|Chiara|C|;Tovo|Pier-Angelo|PA|", "chemical_list": "D000081:Acetamides; D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D023303:Oxazolidinones; D011804:Quinolines; D000069349:Linezolid; D000077266:Moxifloxacin", "country": "United States", "delete": false, "doi": "10.1542/peds.2009-2172", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "126(5)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000081:Acetamides; D000995:Antitubercular Agents; D001372:Aza Compounds; D002675:Child, Preschool; D054242:Emigrants and Immigrants; D005260:Female; D024841:Fluoroquinolones; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007558:Italy; D000069349:Linezolid; D008297:Male; D008826:Microbial Sensitivity Tests; D008966:Moldova; D000077266:Moxifloxacin; D023303:Oxazolidinones; D011804:Quinolines; D012383:Romania; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant", "nlm_unique_id": "0376422", "other_id": null, "pages": "e1253-6", "pmc": null, "pmid": "20974784", "pubdate": "2010-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Two pediatric cases of multidrug-resistant tuberculosis treated with linezolid and moxifloxacin.", "title_normalized": "two pediatric cases of multidrug resistant tuberculosis treated with linezolid and moxifloxacin" }

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{ "abstract": "We report a case of fatal chronic Candida dubliniensis meningitis complicated by severe hydrocephalus secondary to liver transplantation, in which diagnosis was considerably delayed.", "affiliations": "Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.;Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.", "authors": "Gheshlaghi|Mariam|M|;Helweg-Larsen|Jannik|J|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2019.12.009", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30111-310.1016/j.mmcr.2019.12.009Case ReportFatal chronic meningitis caused by Candida dubliniensis after liver transplantation Gheshlaghi Mariam Helweg-Larsen Jannik [email protected]∗Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark∗ Corresponding author. [email protected] 12 2019 3 2020 17 12 2019 27 22 24 26 10 2019 5 12 2019 16 12 2019 © 2019 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of fatal chronic Candida dubliniensis meningitis complicated by severe hydrocephalus secondary to liver transplantation, in which diagnosis was considerably delayed.\n\nKeywords\nCandida dubliniensis meningitisChronic meningitisLiver transplantationInvasive candidiasis\n==== Body\n1 Introduction\nChronic meningitis caused by candida is rare and often difficult to diagnose. Candida dubliniensis meningitis has only been described in very few cases. We report a case of fatal chronic C. dubliniensis meningitis complicated by hydrocephalus secondary to liver transplantation, in which diagnosis was considerably delayed. To our knowledge, this is the seventh reported case of C. dubliniensis meningitis [[1], [2], [3], [4], [5], [6]].\n\n1.1 Case\nThree months after liver transplantation, a 32-year-old male was admitted (day 0) because of four weeks of headache, nausea and intermittent fever. His previous medical history included ulcerative colitis, diabetes and progressive liver failure secondary to primary sclerosing cholangitis with autoimmune hepatitis. After liver transplantation, recovery was delayed because of biliary strictures and cholangitis from which he recovered without signs of rejection or invasive candidiasis. Before admission, standard dosages of tacrolimus, mycophenolate mofetil and prednisone were used for the prevention of rejection. No antifungal prophylaxis was given.\n\nOn admission, his headache was severe, but neurological examination was unremarkable. Lumbar puncture revealed a cerebrospinal fluid (CSF) white cell count of 438 × 106 with 55% neutrophils, protein 1.1 g/L and glucose 3.0 mmol/L (Table 1). Microscopy, extended CSF cultures and broad-range PCR were negative for bacteria, vira and fungi. CT and MRI of the brain as well as CSF opening pressure were normal. Empirical treatment with meropenem, ciprofloxacin and acyclovir were initiated without improvement. Subsequently, lumbar punctures were repeated, which demonstrated decreasing pleocytosis and increasing CSF protein, but remained negative by culture and PCR. Repeated MRI and CT was also unremarkable. CSF opening pressure was not at this time measured. Initially, the severity headache was fluctuating, but worsened at day +21 with development of hydrocephalus, requiring external ventricular drainage (EVD). At day +28, a fourth CSF culture finally grew C. dubliniensis, which at this time also was detected by 18s rRNA PCR of the CSF. Species identification was done at the National Reference Unit of Mycology, Statens Serum Institut, as previously reported [7]. Beta-D-glucan testing was not performed.Table 1 Cerebrospinal fluid findings.\n\nTable 1Week of admission\tNucleated cells (x 10 6/l)\tNeutrophils (x 106/l)\tProtein (g/dl)\tMicrobiology\t\n1\t438\t243\t1.05\tNegative\t\n2\t269\t101\t1.21\tNegative\t\n3\t211\t99\t1.62\tNegative\t\n4\t91\t43\t0.66\tCulture/PCR 18s rRNA d\t\n5\t244\t217\t0.77\ta Culture d\t\n6\t119\t96\t0,86\t–\t\n7\t45\t22\t0.52\t–\t\n8\t16\t11\t0.26\t–\t\n9\t20\t11\t0.23\t–\t\n10\t73\t42\t>6\t–\t\n11\t49\t37\t2\t–\t\n12\t292\t173\t>6\t-b\t\n13\t–\t–\t–\t–\t\n14\t–\t–\t–\t–\t\n15\t66\t24\t>6\t–\t\n16\t20\t13\t0.19\tc\t\n17\t67\t35\t0.45\t–\t\n18\t32\t12\t0.58\t\t\nCandida dubliniensis, sensitive to Voriconazol (MIC: 0.008 mg/L), Amphotericin B (MIC: 0.032 mg/L), Fluconazol (MIC: 0.125 mg/L).The majority of CSF samples after week 4 were obtained from external ventricular drainage.\n\na After 3 days of treatment.\n\nb PCR negative.\n\nc A few yeasts by microscopy. CSF culture negative, Candida mannan antigen in CSF >500 pg/ml. PCR not done.\n\nd Positive. - Culture negative.\n\n\n\nTreatment with ambisome and flucytosine was initiated and the EVD drain was changed with addition of intrathecal amphotericin B. Because of persistent side-effects, flucytosine was replaced with high dose fluconazole. Repeated attempts of EVD weaning failed because of persisting hydrocephalus, which lead to placement of a ventriculoperitoneal (VP) shunt. At this time, the patient's condition improved somewhat. Repeated CSF cultures were negative, but CSF inflammation persisted (Table 1). At day +70, MRI demonstrated subarachnoidal leptomeningeal enhancement and discrete signal changes in the medulla oblongata. Amphotericin B was discontinued after +84 days of treatment and fluconazole 800 mg x1 was continued. During the next weeks, his clinical condition deteriorated again with MRI showing severe enhancement and oedema at the cisterna magna with stenosis of the aqueduct. Treatment with Amphotericin B and flucytosine was restarted, the VP shunt was removed, and intrathecal caspofungin was added. Empiric antibiotics for suspected EVD associated ventriculitis was also given.\n\nDespite aggressive antifungal therapy, his condition deteriorated slowly with increasing double vision, memory loss and tremors. By MRI increased blockage of the foramen Monroe and oedema of the medulla oblongata was found. A few yeasts and an elevated Candida mannan antigen level were at this time detected in the CSF, but cultures remained negative. Further reduction of the immunosuppressive therapy was attempted, however, acute on chronic liver graft rejection developed and the patient died shortly after. Investigations (without DNA sequencing) for primary immunodeficiencies were negative.\n\n2 Discussion\nCandida is as rare cause of CNS infection among immunocompromised patients and associated with mortality rates over 50% [8,9]. Usually, candida meningitis is caused by C.albicans, however cases of C. dubliniensis have been reported after 2008, in which the first case was described [1]. C. dubliniensis is closely related to C. albicans, which it resembles by the ability to produce hyphae and chlamydospores. Infection models have suggested that C. dubliniensis is less pathogenic than C. albicans [10]. However, invasive candidiasis (IC) caused by non-albicans species are increasing [11,12]. A recent Danish nationwide study observed a doubling in the incidence of C. dubliniensis fungemia from 2012 to 2015 [12]. Previous reports of C. dubliniensis meningitis have been related to heart and lung transplantation [1,4], IVDU [5,6], CARD 9 immunodeficiency [3] and cirrhosis [2]. In two of these cases, relapse of C. dubliniensis meningitis was observed after 8 week and 6 months of initial therapy, respectively.\n\nThe diagnosis of candida as a cause of chronic meningitis is often challenging. In most cases, initial CSF findings are pleocytosis with granulocyte predominance and diagnosis may be delayed due to negative CSF culture. In the present case, several repeated CSF cultures and PCR were negative before the final verification of C.dubliniensis. Similar difficulties have been described previously. In a case of C. albicans meningitis secondary to liver transplantation reported by Ralph et al., biopsy from the brain and meninges and four repeated CSF cultures were culture and microscopy negative before CSF grew C. albicans [13]. More recently, Wilson et al. reported a 26-year-old IVDU with diffuse brainstem and spinal cord leptomeningitis in which C. dubliniensis was first established by metagenomic next-generation sequencing of CSF after 6 months of extensive negative diagnostic studies including repeated cultures, CSF 18s/6s rRNA PCR and meningeal biopsies [5].\n\nDespite development of severe meningitis and hydrocephalus, initial repeated MRI did not show meningeal inflammation or raised ICP, similar to other case reports [13]. The present case of candida meningitis has several clinical features similar to cryptococcal meningitis in which initial MRI and CSF opening pressure may fail to demonstrate meningitis with raised CNS ICP, and in which hydrocephalus is associated with high mortality [[14], [15], [16], [17]].\n\nThe optimal treatment of candida meningitis is not established, but usually requires intensive prolonged treatment with combination fungicidal treatment such as amphotericin B and flucytosine. In this case, a combination of complicated hydrocephalus, antifungal treatment toxicity and liver failure was fatal despite negative CSF cultures during high-dose systemic combination and intra-thecal antifungal therapy.\n\nThe reason for candida meningitis in the present case is unclear. Candida meningitis is caused by hematogenous spread with secondary cross of the blood brain barrier after which, Candida is able to form biofilms that evade the CNS microglial defense [18]. However, in several case reports, preceding candidemia/IC were not observed. Although liver transplantation is associated with higher risk of invasive fungal infections compared to other SOT, our patient was young, had no previous evidence of IC and did only receive routine immunosuppressive treatment [19,20] In theory, the patient may have had an innate immunodeficiency in keeping with his history of autoimmune hepatitis and colitis ulcerosa, however permission to DNA exome sequencing was not granted.\n\nC. dubliniensis as a cause of chronic meningitis remains rare but appears to be increasing in parallel with the increase in non-albicans invasive candidiasis. Diagnosis and management remain challenging, particularly in case of complicated hydrocephalus, which in our patient was fatal. In culture negative chronic meningitis, candida should be considered and may require repeated CSF investigations. Recent publications have suggested that molecular methods such as metagenomic next-generation sequencing may facilitate early diagnosis [5], however the diagnostic performance of DNA based CSF methods are not established, as shown in our case, in which initial PCR analysis were negative and it remains important to obtain large CSF volumes for specific fungal culturing.\n\nDeclaration of competing interest\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 van Hal S.J. Stark D. Harkness J. Marriott D. Candida dubliniensis meningitis as delayed sequela of treated C. dubliniensis fungemia Emerg. Infect. Dis. 14 2008 327 329 18258133 \n2 Yamahiro A. Lau K.H.V. Peaper D.R. Villanueva M. Meningitis caused by Candida dubliniensis in a patient with cirrhosis: a case report and review of the literature Mycopathologia 181 2016 589 593 27038312 \n3 Drewniak A. Gazendam R.P. Tool A.T.J. van Houdt M. Jansen M.H. van Hamme J.L. van Leeuwen E.M.M. Roos D. Scalais E. de Beaufort C. Janssen H. van den Berg T.K. Kuijpers T.W. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency Blood 121 2013 2385 2392 23335372 \n4 Herrera S. Pavone P. Kumar D. Singer L. Humar A. Chaparro C. Keshavjee S. Husain S. Rotstein C. Chronic Candida dubliniensis meningitis in a lung transplant recipient Med. Mycol. Case Rep. 24 2019 41 43 30976504 \n5 Wilson M.R. O'Donovan B.D. Gelfand J.M. Sample H.A. Chow F.C. Betjemann J.P. Shah M.P. Richie M.B. Gorman M.P. Hajj-Ali R.A. Calabrese L.H. Zorn K.C. Chow E.D. Greenlee J.E. Blum J.H. Green G. Khan L.M. Banerji D. Langelier C. Bryson-Cahn C. Harrington W. Lingappa J.R. Shanbhag N.M. Green A.J. Brew B.J. Soldatos A. Strnad L. Doernberg S.B. Jay C.A. Douglas V. Josephson S.A. DeRisi J.L. Chronic meningitis investigated via metagenomic next-generation sequencing JAMA Neurol. 75 2018 947 955 29710329 \n6 Andrew N.H. Ruberu R.P. Gabb G. The first documented case of Candida dubliniensis leptomeningeal disease in an immunocompetent host BMJ Case Rep. 2011 4 7 \n7 Arendrup M.C. Dzajic E. Jensen R.H. Johansen H.K. Kjældgaard P. Knudsen J.D. Kristensen L. Leitz C. Lemming L.E. Nielsen L. Olesen B. Rosenvinge F.S. Røder B.L. Schønheyder H.C. Epidemiological changes with potential implication for antifungal prescription recommendations for fungaemia: data from a nationwide fungaemia surveillance programme Clin. Microbiol. Infect. 19 2013 \n8 Voice R.A. Bradley S.F. Sangeorzan J.A. Kauffman C.A. Chronic candidal meningitis: an uncommon manifestation of candidiasis Clin. Infect. Dis. 19 1994 60 66 7948559 \n9 Góralska K. Blaszkowska J. Dzikowiec M. Neuroinfections caused by fungi Infection 46 2018 443 459 29785613 \n10 Moran G.P. Coleman D.C. Sullivan D.J. Candida albicans versus Candida dubliniensis: why Is C. albicans more pathogenic? Internet J. Microbiol. 2012 2012 \n11 Khan Z. Ahmad S. Joseph L. Chandy R. Candida dubliniensis: an appraisal of its clinical significance as a bloodstream pathogen PLoS One 7 2012 e32952 \n12 Astvad K.M.T. Johansen H.K. Røder B.L. Rosenvinge F.S. Knudsen J.D. Lemming L. Schønheyder H.C. Hare R.K. Kristensen L. Nielsen L. Gertsen J.B. Dzajic E. Pedersen M. Østergård C. Olesen B. Søndergaard T.S. Arendrup M.C. Update from a 12-year nationwide fungemia surveillance: increasing intrinsic and acquired resistance causes concern J. Clin. Microbiol. 56 2018 1 15 \n13 Ralph E.D. Hussain Z. Chronic meningitis caused by Candida albicans in a liver transplant recipient: usefulness of the polymerase chain reaction for diagnosis and for monitoring treatment Clin. Infect. Dis. 23 1996 191 192 8816159 \n14 Sarkis R.A. Mays M. Isada C. Ahmed M. MRI findings in cryptococcal meningitis of the non-HIV population The Neurologist 19 2015 40 45 25607331 \n15 Williamson P.R. Jarvis J.N. Panackal A.A. Fisher M.C. Molloy S.F. Loyse A. Harrison T.S. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy Nat. Rev. Neurol. 13 2017 13 24 27886201 \n16 Loyse A. Moodley A. Rich P. Molloy S.F. Bicanic T. Bishop L. Rae W.I.D. Bhigjee A.I. Loubser N.D. Michowicz A.J. Wilson D. Harrison T.S. Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis J. Infect. 70 2015 668 675 25444972 \n17 Cherian J. Atmar R.L. Gopinath S.P. Shunting in cryptococcal meningitis J. Neurosurg. 125 2016 177 186 26517766 \n18 Koutsouras G.W. Ramos R.L. Martinez L.R. Role of microglia in fungal infections of the central nervous system Virulence 8 2017 705 718 27858519 \n19 Nagao M. Fujimoto Y. Yamamoto M. Matsumura Y. Kaido T. Takakura S. Uemoto S. Ichiyama S. Epidemiology of invasive fungal infections after liver transplantation and the risk factors of late-onset invasive aspergillosis J. Infect. Chemother. 22 2016 84 89 26683245 \n20 Pappas P.G. Alexander B.D. Andes D.R. Hadley S. a Kauffman C. Freifeld A. Anaissie E.J. Brumble L.M. Herwaldt L. Ito J. Kontoyiannis D.P. Lyon G.M. a Marr K. a Morrison V. Park B.J. Patterson T.F. Perl T.M. a Oster R. Schuster M.G. Walker R. Walsh T.J. a Wannemuehler K. Chiller T.M. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clin. Infect. Dis. 50 2010 1101 1111 20218876\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "27()", "journal": "Medical mycology case reports", "keywords": "Candida dubliniensis meningitis; Chronic meningitis; Invasive candidiasis; Liver transplantation", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "22-24", "pmc": null, "pmid": "31890490", "pubdate": "2020-03", "publication_types": "D002363:Case Reports", "references": "25607331;7948559;26683245;22396802;23607326;18258133;26517766;27886201;30976504;23335372;20218876;29212705;8816159;27038312;29785613;25444972;29710329;22687683;21904553;27858519", "title": "Fatal chronic meningitis caused by Candida dubliniensis after liver transplantation.", "title_normalized": "fatal chronic meningitis caused by candida dubliniensis after liver transplantation" }

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CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CASPOFUNGIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (EMPIRICAL TREATMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (EMPIRICAL TREATMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS CANDIDA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMBISOME" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (STANDARD DOSAGES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "GHESHLAGHI, M.. FATAL CHRONIC MENINGITIS CAUSED BY CANDIDA DUBLINIENSIS AFTER LIVER TRANSPLANTATION.. MEDICAL MYCOLOGY CASE REPORTS. 2020?27:10.1016/J.MMCR.2019.12.009", "literaturereference_normalized": "fatal chronic meningitis caused by candida dubliniensis after liver transplantation", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20200121", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17268686, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "DK-TEVA-2020-DK-1171197", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Aqueductal stenosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Amnesia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis candida", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "GHESHLAGHI M, HELWEG-LARSEN J. FATAL CHRONIC MENINGITIS CAUSED BY CANDIDA DUBLINIENSIS AFTER LIVER TRANSPLANTATION. MED-MYCOL-CASE-REPORTS 2020?27:22-24.", "literaturereference_normalized": "fatal chronic meningitis caused by candida dubliniensis after liver transplantation", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20200122", "receivedate": "20200122", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17301139, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "BACKGROUND\nClinical trials evaluating the efficacy of dabigatran followed a very strict protocol, which included close monitoring and follow-up. Patients followed in this controlled environment had an average medication possession ratio (MPR) greater than 0.95. However, very few studies have evaluated patient adherence to dabigatran in a real-world setting. Other studies of chronic medications indicate patients are not reliably adherent to twice daily regimens. Adherence to therapy is particularly important for direct thrombin inhibitors because there may be a risk of increased thromboembolic events associated with poor adherence to these agents.\n\n\nOBJECTIVE\nTo identify the MPR for patients prescribed dabigatran at a large academic medical center and affiliated clinics.\n\n\nMETHODS\nThis retrospective descriptive study evaluated the MPR for patients prescribed dabigatran between January 1, 2012, and December 31, 2012. Patients included in this study had to receive dabigatran for a minimum of 3 months, have a primary care physician or cardiologist at the medical center or affiliated clinics, and must not use a mail order pharmacy. Patient MPR was calculated based on prescriptions picked up from the patient.\n\n\nRESULTS\nAfter screening 400 patients, 159 patients met eligibility criteria. The mean MPR for the patients in this study was 0.63. Overall, 43% of the patients had an MPR of less than 0.80, and the mean MPR for this subgroup was 0.39 ± 0.27; 57% of the study population had an MPR of 0.80 or higher, with a mean MPR of 0.94 ± 0.08. There was a significantly higher proportion of men (67.7%, P = 0.0112) and a larger number of \"as needed medications\" prescribed (1.73 vs. 0.86, P = 0.0039) in patients with an MPR less than 0.80. There were 5 patients hospitalized during the study period (3 for bleeding, 1 for confusion, and 1 death not related to dabigatran therapy).\n\n\nCONCLUSIONS\nThe relatively low mean MPR seen in this study may indicate that there is a need for improved anticoagulation services and follow-up for patients taking dabigatran.", "affiliations": "UCSF School of Pharmacy, 521 Parnassus Ave., Box 0622, San Francisco, CA 94143,USA. [email protected].", "authors": "Cutler|Timothy W|TW|;Chuang|Alan|A|;Huynh|Tony D|TD|;Witt|Robert G|RG|;Branch|Jennifer|J|;Pon|Tiffany|T|;White|Richard|R|", "chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran", "country": "United States", "delete": false, "doi": "10.18553/jmcp.2014.20.10.1028", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "20(10)", "journal": "Journal of managed care & specialty pharmacy", "keywords": null, "medline_ta": "J Manag Care Spec Pharm", "mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D012189:Retrospective Studies; D013923:Thromboembolism; D015091:beta-Alanine", "nlm_unique_id": "101644425", "other_id": null, "pages": "1028-34", "pmc": null, "pmid": "25278325", "pubdate": "2014-10", "publication_types": "D016428:Journal Article", "references": null, "title": "A retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center.", "title_normalized": "a retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center" }

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{ "abstract": "If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission.\n\n\n\nTo investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi.\n\n\n\nOpen-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS < 1.6) at week 50.\n\n\n\nEight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308).\n\n\n\nRemission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients.\n\n\n\nRegistered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.", "affiliations": "Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.;Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.;Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam, the Netherlands.;Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, the Netherlands.;Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam, the Netherlands.;Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.;Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. [email protected].", "authors": "de Jong|Henriëtte M Y|HMY|0000-0003-1818-180X;van Mens|Leonieke J J|LJJ|;Nurmohamed|Michael T|MT|;Kok|Marc R|MR|;van Kuijk|Arno W R|AWR|;Baeten|Dominique L P|DLP|;van de Sande|Marleen G H|MGH|", "chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors; C529000:golimumab; D008727:Methotrexate", "country": "England", "delete": false, "doi": "10.1186/s13075-019-1998-4", "fulltext": "\n==== Front\nArthritis Res TherArthritis Res. TherArthritis Research & Therapy1478-63541478-6362BioMed Central London 199810.1186/s13075-019-1998-4Research ArticleSustained remission with methotrexate monotherapy after 22-week induction treatment with TNF-alpha inhibitor and methotrexate in early psoriatic arthritis: an open-label extension of a randomized placebo-controlled trial http://orcid.org/0000-0003-1818-180Xde Jong Henriëtte M. Y. 12van Mens Leonieke J. J. 12Nurmohamed Michael T. 234Kok Marc R. 5van Kuijk Arno W. R. 24Baeten Dominique L. P. 12van de Sande Marleen G. H. [email protected] 121 0000000084992262grid.7177.6Department of Clinical Immunology and Rheumatology, Infection & Immunity Institute, Amsterdam UMC, AMC/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands 2 0000 0004 0435 165Xgrid.16872.3aAmsterdam Rheumatology & Immunology Center (ARC), Amsterdam, the Netherlands 3 0000 0004 1754 9227grid.12380.38Department of Rheumatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 4 0000 0004 0624 3484grid.418029.6Department of Rheumatology, Reade, Amsterdam, the Netherlands 5 0000 0004 0460 0556grid.416213.3Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, the Netherlands 14 9 2019 14 9 2019 2019 21 20818 6 2019 5 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIf TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission.\n\nObjective\nTo investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi.\n\nMethods\nOpen-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS < 1.6) at week 50.\n\nResults\nEight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308).\n\nConclusions\nRemission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients.\n\nTrial registration\nRegistered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.\n\nKeywords\nEarly psoriatic arthritisRemissionTreatment withdrawalMethotrexateTNF inhibitorhttp://dx.doi.org/10.13039/100009947Merck Sharp and DohmeNAissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nBiologics have drastically changed the field of rheumatology. Whereas they have originally been used to treat patients who were refractory to classical disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX), increasing evidence shows that their use in early disease allows to achieve high remission rates [1–4]). Moreover, it has been postulated that if biologics are initiated in the early stages of disease, during the so-called window of opportunity [5], this could promote an immune reset rather than merely suppression of inflammation and thereby alter the course of the disease and allow for discontinuation of treatment in patients who achieve remission.\n\nMost of the studies exploring these concepts have been conducted in rheumatoid arthritis. It remains unclear to what extent these concepts may also apply to psoriatic arthritis (PsA), a subgroup of spondyloarthritis that can present with skin and nail psoriasis, arthritis, enthesitis, dactylitis, and axial disease [6].\n\nWe recently demonstrated that initiation of tumor necrosis factor alpha inhibition (TNFi) with golimumab in combination with MTX doubled the number of early PsA patients achieving Disease Activity Score (DAS) remission at week 22 in comparison with MTX monotherapy from 42% with MTX alone to 81% with golimumab plus MTX combination therapy [4]. To explore the hypothesis that remission induced by TNFi plus MTX in patients with early psoriatic arthritis can be sustained after withdrawal of TNFi, we conducted an open-label extension study of this trial with patients that were in DAS-CRP remission at week 22 and continued on MTX monotherapy. Disease activity was assessed at weeks 36 and 50.\n\nMethods\nStudy design and patients\nThe original study design and baseline characteristics have been described in detail [4]. In short, 51 patients with psoriatic arthritis (PsA), fulfilling the CASPAR criteria and with active disease (defined as swollen and tender joint count ≥ 3), were included. During the double-blind phase (up to week 22), all patients received methotrexate (MTX) up to 25 mg/week and were randomized to either golimumab 50 mg/month (n = 26) or matched placebo (n = 24). Patients with a status of DAS-CRP remission at week 22, defined by a DAS-CRP score < 1.6, were offered to enter the open-label extension phase up to week 50 on MTX monotherapy. A clinical assessment was done at week 36 and week 50, and an additional visit was done in the case of worsening or recurrence of symptoms. Participants who had loss of remission were withdrawn from the trial. The group that originally used MTX and placebo will further be referred to as the ‘original MTX group’, and the group that used methotrexate and golimumab will further be referred to as the ‘original MTX+TNFi group’.\n\nThis study was conducted at three centres in the Netherlands between September 2013 and September 2017 and was approved by the Medical Ethics Committee of the Academic Medical Centre in Amsterdam. Written informed consent was obtained from each patient before enrolment. The study was conducted in compliance with the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki and is registered at clinicaltrials.gov under NCT01871649.\n\nAssessments\nThe primary efficacy end point of this study was the percentage of patients who sustained a status of DAS-CRP remission [7] (DAS-CRP score < 1.6) at week 50. Secondary efficacy end points included Low Disease Activity (LDA) status (DAS-CRP < 2.4), criteria for Minimal Disease Activity (MDA) [8], and Disease Activity in Psoriatic Arthritis Low Disease Activity (DAPSA-LDA) [9]. Clinical evaluations, patient-reported outcomes, and standard laboratory tests were done at every study visit. Safety end points included adverse events (AEs) and serious AEs (SAEs) and discontinuation or interruption of study treatment.\n\nStatistical analysis\nData are presented as mean (SD) unless indicated otherwise. Differences between both groups were analysed with a chi-square test for categorical data and a Mann-Whitney U test for continuous data. The primary and secondary outcomes were analysed with an intention-to-treat analysis. Patients that discontinued for any reason during the extension study were considered non-responders, as were patients that were in remission at week 22 but did not attend a study visit during the extension study. All statistical tests were two sided, and a p value of < 0.05 was considered statistically significant.\n\nResults\nStudy population and patient disposition\nThe patient disposition and flow chart are summarized in Fig. 1. Ten patients from the original MTX group achieved remission in the first 22 weeks of the study. Of those, 2 were lost to follow-up. Therefore, 8 patients from the original MTX group entered the extension phase, of whom 6 completed week 50. For the original MTX+TNFi group, 21 patients achieved remission in the first 22 weeks of the study. Three were excluded before the start of the extension phase; therefore, 18 patients entered the extension phase, of whom 10 completed week 50.\nFig. 1 The patient disposition and flow chart\n\n\n\nBaseline characteristics of the total study cohort have been described previously [4]. Table 1 shows demographics, disease characteristics, and disease activity measures of the 26 patients (18 from the original MTX+TNFi group and 8 from the original MTX group) continuing in the extension phase for baseline and weeks 22, 36, and 50 (data as observed). Demographics did not differ between both groups. At baseline VAS, patient pain was lower in the original MTX group compared to that in the original MTX+TNFi group (p = 0.011), as was the BASDAI (p = 0.047). At week 22, PASI score was significantly higher in the original MTX group (p = 0.001). At weeks 36 and 50, there were no differences between both groups. The overall mean (SD) dosage of methotrexate in the extension phase was comparable in both groups: 22.5 (4.9) mg/week in the original MTX group and 20.9 (6.2) mg/week in the original MTX+TNFi group (non-significant).\nTable 1 Demographics, characteristics, and disease activity measures as observed on patients who entered the extension study\n\n\tBaseline\tWeek 22\tWeek 36\tWeek 50\t\nOriginal MTX (n = 8)\tOriginal MTX+TNFi (n = 18)\t\np\n\tOriginal MTX (n = 8)\tOriginal MTX+TNFi (n = 18)\t\np\n\tOriginal MTX (n = 8)\tOriginal MTX+TNFi (n = 16)\t\np\n\tOriginal MTX (n = 6)\tOriginal MTX+TNFi (n = 10)\t\np\n\t\nAge\t46 (13.1)\t48.7 (10)\tNS\t\t\t\t\t\t\t\t\t\t\nGender (male/female)\t7/1\t13/5\tNS\t7/1\t13/5\tNS\t7/1\t13/3\tNS\t5/1\t9/1\tNS\t\nDisease duration < 2 years, n (%)\t5 (62.5)\t14 (77.8)\tNS\t5 (62.5)\t14 (77.8)\tNS\t5 (62.5)\t12 (75)\tNS\t4 (66.7)\t6 (60)\tNS\t\nSJC 66, median (IQR)\t3.5 (3–7.3)\t7 (4–8.3)\tNS\t0.5 (0–2)\t0 (0–1)\tNS\t1 (0.3–2)\t0 (0–1.3)\tNS\t0 (0–1.3)\t0 (0–3.3)\tNS\t\nTJC 68, median (IQR)\t5 (4–13.8)\t10 (4.8–14.3)\tNS\t1 (0.3–3.3)\t0 (0–3.3)\tNS\t1.5 (0.3–2.8)\t1.5 (0–4.5)\tNS\t0 (0–1.5)\t1.5 (0–4.3)\tNS\t\nPASI score, median (IQR)\t2.7 (0.5–6)\t1.9 (0.8–3.8)\tNS\t0.8 (0.4–1.7)\t0\t0.001\t0.5 (0.5–1.8)\t0\tNS\t1 (0.3–1.9)\t0.6 (0–1.3)\tNS\t\nPASI > 2.5, n (%)\t4 (50)\t8 (44.4)\tNS\t1 (12.5)\t0\tNS\t0\t1 (6.3)\tNS\t0\t1 (10)\tNS\t\nPts with enthesitis, n (%)\t0\t2 (11.1)\tNS\t1 (12.5)\t1 (5.6)\tNS\t1 (12.5)\t3 (18.9)\tNS\t0\t1 (10)\tNS\t\nPts with dactylitis, n (%)\t4 (50)\t4 (22.2)\tNS\t1 (12.5)\t0\tNS\t4 (50)\t1 (6.3)\tNS\t1 (16.7)\t1 (10)\tNS\t\nESR (mm/h), median (IQR)\t15.5 (5.5–24.3)\t20.5 (4.3–31.8)\tNS\t7 (3.5–15.8)\t2 (2–18)\tNS\t5.5 (2–10.8)\t5 (2–6.5)\tNS\t5 (2.5–11.5)\t6 (2–12)\tNS\t\nCRP (mg/L), median (IQR)\t9.5 (2.1–14)\t4 (1.3–14.5)\tNS\t3.1 (0.9–15)\t1.1 (0.4–2.9)\tNS\t1.8 (0.7–8)\t1.5 (0.4–4)\tNS\t4.2 (0.9–7.4)\t2 (1–5)\tNS\t\nVAS patient global (mm)\t26.9 (17.8)\t46.3 (24.9)\tNS\t23.4 (25.9)\t17.7 (17.6)\tNS\t18.3 (20.9)\t24.1 (23.8)\tNS\t17.4 (15.2)\t19.8 (20)\tNS\t\nVAS patient pain (mm)\t20 (15.8)\t47.7 (26.1)\t0.011\t8.1 (12.7)\t13.6 (17.5)\tNS\t9.4 (8.7)\t23 (21.6)\tNS\t6.2 (4)\t21 (27.1)\tNS\t\nVAS physician (mm)\t43.1 (14.0)\t45.3 (15.6)\tNS\t12.6 (10.2)\t8.1 (9.3)\tNS\t8.9 (8.1)\t13.8 (19.6)\tNS\t15.6 (12.1)\t13 (17.5)\tNS\t\nBASDAI\t2.4 (1.8)\t4.1 (1.9)\t0.047\t1.5 (1.6)\t1.8 (1.5)\tNS\t1.7 (1.5)\t2 (1.7)\tNS\t1.8 (1.7)\t1.7 (1.4)\tNS\t\n\n\nSafety\nDuring the extension phase, one serious adverse event (SAE) occurred in a patient from the original MTX+TNFi group: a small bowel obstruction with surgical intervention, which was judged unrelated to the study and did not lead to early termination. Eighteen AEs occurred during the extension phase: 9 in the original MTX+TNFi group and 9 in the original MTX group. One patient from the original MTX+TNFi group discontinued after week 40 because of an AE related to the study medication (liver enzymes > 2 times the upper limit of normal).\n\nEfficacy\nSix out of 8 (75%) patients from the original MTX group completed the extension study and maintained DAS remission at week 50. Five out of 6 fulfilled criteria for MDA, and all were in DAPSA-LDA. Two patients had a loss of DAS remission at week 36; 1 had a status of LDA according to the DAS, 1 was in DAPSA-LDA, and none were in MDA.\n\nTen out of 18 patients (56%) from the original MTX+TNFi group completed the extension study and maintained DAS remission at week 50. Six out of 10 fulfilled the criteria for MDA, and 7 out of 10 were in DAPSA-LDA. Of the 8 patients dropping out of this arm of the study, 3 patients discontinued while still in DAS remission but were considered non-responders in the intention-to-treat analysis: 1 discontinued because of an AE (week 40) and 2 discontinued upon their own request (weeks 29 and 36) (Fig. 1). Five patients had a loss of DAS remission (1 at week 29, 3 at week 36, and 1 at week 45); 4/5 patients had a status of LDA according to the DAS, 1/5 was in MDA, and 3/5 in DAPSA-LDA.\n\nIn the intention-to-treat analysis, 6/8 (75%) patients from the original MTX group versus 10/18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission at week 50 (p = 0.347). Considering not only the extension phase but the complete study from baseline to week 50, 6/24 (25%) patients from the original MTX group had a status of DAS-CRP remission at week 50 compared to 10/26 (38%) patients from the original MTX+TNFi group (p = 0.308).\n\nDiscussion\nWe recently reported that initiating combination therapy with MTX+TNFi resulted in doubling the rate of DAS-CRP remission at week 22 (81%) compared to MTX alone in patients (42%) with early psoriatic arthritis (PsA). We hypothesized that achieving remission in this ‘window of opportunity’ would allow to maintain clinical benefit in a substantial number of patients even after stopping the TNFi at week 22. Here we report that 56% of those patients indeed maintained remission up to week 50, whereas 75% of the patient achieving remission at week 22 on MTX monotherapy maintained remission over time. Taking into account the total study population, 38% of the original MTX+TNFi group versus 25% of the original MTX group achieved and maintained remission up to week 50.\n\nA number of important aspects should be taken into consideration when interpreting the data of the present study. First, the number of patients included in the extension phase of the study was small, especially in the original MTX monotherapy group. Second, the study did not assess drug-free remission as all patients were on continuous MTX therapy from baseline to week 50 to reflect standard of care; the study was not designed to assess the real efficacy of MTX. Continuation of MTX in all patients also explains the high maintenance of remission in the original MTX group, as there was no drug withdrawal in this group, only withdrawal of the placebo. Third, the patients and investigators remained blinded during the whole study (up to week 50) for the golimumab versus placebo treatment in the induction phase of the study, but were aware that this initial treatment was withdrawn at week 22. Fourth, we used the most conservative version of the data to do the analyses. Two patients from the original MTX+TNFi group who experienced a flare during the extension phase were actually still in DAS remission, but were nevertheless withdrawn from the study by the study physician because of arthritis in multiple joints not included in the DAS. Although still formally in DAS remission, these patients were considered as having a loss of remission in the analyses. Also patients dropping out for other reasons were considered as non-responders.\n\nDespite these caveats, our findings are concordant with several other studies in PsA and other types of spondyloarthritis [10–12]). Huynh et al. reported that 55.1% of patients with PsA who discontinued TNFi had persistent clinical benefit of TNFi therapy at the last clinical visit. In this study, smoking and higher disease activity at the time of discontinuation were predictors of loss of clinical benefit, but disease duration did not affect the outcome [10].\n\nThe data of the current trial fail to support the hypothesis of immune reset by early TNFi treatment in PsA. In summary, our findings indicate that it is possible to maintain remission on MTX monotherapy in a substantial number of patients with early PsA achieving remission by initial combination treatment with TNFi and methotrexate. However, for how long this remission can be maintained and whether the maintained remission in these patients is due to an immune reset or merely due to suppression of inflammation is not known. Moreover, a fair number of patients in the original MTX+TNFi lost remission after stopping TNFi, which shows that our treatment strategy did not provide the ‘window of opportunity’ to change the disease course in all patients. Whether even earlier initiated (combination) treatment or other targeted treatment could provide a ‘window of opportunity’ with sustained remission in all patients needs further assessment in future treatment strategy trials.\n\nAbbreviations\nTNFiTumour necrosis factor inhibitor\n\nPsAPsoriatic arthritis\n\nMTXMethotrexate\n\nDMARDsDisease-modifying anti-rheumatic drugs\n\nDASDisease Activity Score\n\nCRPC-reactive protein\n\nMDAMinimal Disease Activity\n\nLDALow Disease Activity\n\nDAPSA-LDADisease Activity in Psoriatic Arthritis Low Disease Activity\n\nAEAdverse event\n\nSAESerious adverse event\n\nVASVisual analogue scale\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank all patients that participated in this study and their treating physicians who referred patients. Also we thank Inka Fluri and Maureen Leeuw for their contribution to this study.\n\nAuthors’ contributions\nThe study protocol was designed by DL, LvM, MN, MK, and AvK. LvM, MN, MK, AvK, and MvS recruited and selected patients. Data interpretation was done by HdJ, LvM, DL, and MvS. The manuscript was primarily drafted by HdJ. All authors have read and approved the final version of this manuscript.\n\nFunding\nThis investigator-initiated study was supported by supply of study medication and an unrestricted grant from MSD.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was approved by the Medical Ethics Committee of the Academic Medical Center in Amsterdam. All patients provided written informed consent.\n\nConsent for publication\nNot applicable\n\nCompeting interests\nDB is currently an employee of UCB Pharma. LJJvM and HMdJ declare that they have no competing interest. MGHvdS has been an advisor for Abbvie and Novartis and received research grants from Janssen, Eli Lily, and Novartis. The department of MK is supported by Novartis, Abbvie, Pfizer, Roche, Lilly, and BMS, and MK has been an advisor for Novartis and Abbvie. MTN received research grants, consultation, and/or speaking fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Mundipharma, Novartis, Pfizer, Roche, Sanofi, and UCB Pharma. AWRvK received speaker fees from Celgene, Novartis, Eli Lilly, and Janssen and received research support from MSD and Janssen.\n==== Refs\nReferences\n1. Smolen JS Emery P Fleischmann R Van Vollenhoven RF Pavelka K Durez P Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial Lancet 2014 383 321 332 10.1016/S0140-6736(13)61751-1 24168956 \n2. Atsumi T Tanaka Y Yamatomo K Takeuchi T Yamanaka H Ishiguro N Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial Ann Rheum Dis 2017 76 1348 1356 10.1136/annrheumdis-2016-210246 28153828 \n3. Emery P Bingham CO Burmester GR Bykerk VP Furst DE Mariette X Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study Ann Rheum Dis 2017 76 96 104 10.1136/annrheumdis-2015-209057 27165179 \n4. van Mens Leonieke J J de Jong Henriëtte M Fluri Inka Nurmohamed Michael T van de Sande Marleen G H Kok Marc van Kuijk Arno W R Baeten Dominique Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double-blind, randomised, placebo-controlled trial of golimumab plus methotrexate versus placebo plus methotrexate Annals of the Rheumatic Diseases 2019 78 5 610 616 10.1136/annrheumdis-2018-214746 30808625 \n5. Van Nies JAB Tsonaka R Gaujoux-Viala C Fautrel B Van Der Helm-Van Mil AHM Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts Ann Rheum Dis 2015 74 806 812 10.1136/annrheumdis-2014-206047 25561360 \n6. Van den Bosch F Coates L Clinical management of psoriatic arthritis Lancet 2018 391 2285 2294 10.1016/S0140-6736(18)30949-8 29893227 \n7. van Gestel AM Prevoo MLL van’t Hof MA van Rijswijk MH van de Putte LBA van Riel PLCM Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria Arthritis Rheum 1996 39 34 40 10.1002/art.1780390105 8546736 \n8. Coates LC Fransen J Helliwell PS Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment Ann Rheum Dis 2010 69 48 53 10.1136/ard.2008.102053 19147615 \n9. Schoels M Aletaha D Funovits J Kavanaugh A Baker D Smolen JS Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic arthritis Ann Rheum Dis 2010 69 1441 1447 10.1136/ard.2009.122259 20525844 \n10. Huynh DH Boyd TA Etzel CJ Cox V Kremer J Mease P Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis RMD Open 2017 3 1 4 10.1136/rmdopen-2016-000395 \n11. Carron Philippe Varkas Gaëlle Renson Thomas Colman Roos Elewaut Dirk Van den Bosch Filip High Rate of Drug-Free Remission After Induction Therapy With Golimumab in Early Peripheral Spondyloarthritis Arthritis & Rheumatology 2018 70 11 1769 1777 10.1002/art.40573 29806090 \n12. Landewé R Sieper J Mease P Inman RD Lambert RG Deodhar A Efficacy and safety of continuing versus withdrawing adalimumab therapy in maintaining remission in patients with non-radiographic axial spondyloarthritis (ABILITY-3): a multicentre, randomised, double-blind study Lancet 2018 392 134 144 10.1016/S0140-6736(18)31362-X 29961640\n\n", "fulltext_license": "CC BY", "issn_linking": "1478-6354", "issue": "21(1)", "journal": "Arthritis research & therapy", "keywords": "Early psoriatic arthritis; Methotrexate; Remission; TNF inhibitor; Treatment withdrawal", "medline_ta": "Arthritis Res Ther", "mesh_terms": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors", "nlm_unique_id": "101154438", "other_id": null, "pages": "208", "pmc": null, "pmid": "31521192", "pubdate": "2019-09-14", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "29961640;29893227;8546736;28153828;25561360;20525844;28123783;29806090;24168956;27165179;30808625;19147615", "title": "Sustained remission with methotrexate monotherapy after 22-week induction treatment with TNF-alpha inhibitor and methotrexate in early psoriatic arthritis: an open-label extension of a randomized placebo-controlled trial.", "title_normalized": "sustained remission with methotrexate monotherapy after 22 week induction treatment with tnf alpha inhibitor and methotrexate in early psoriatic arthritis an open label extension of a randomized placebo controlled trial" }

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{ "abstract": "After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c-Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed.", "affiliations": "Department of Pathology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Experimental Oncology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Department of Pathology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Medical Oncology B Units, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Medical Oncology B Units, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Department of Pathology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;CRO Aviano National Cancer Institute IRCCS, Scientific Directorate, Aviano, PN, Italy. Electronic address: [email protected].;Experimental Oncology, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].;Medical Oncology B Units, CRO Aviano National Cancer Institute IRCCS, Aviano, PN, Italy. Electronic address: [email protected].", "authors": "Canzonieri|Vincenzo|V|;Gasparotto|Daniela|D|;Alessandrini|Lara|L|;Miolo|Gianmaria|G|;Torrisi|Elena|E|;Perin|Tiziana|T|;De Paoli|Paolo|P|;Maestro|Roberta|R|;Buonadonna|Angela|A|", "chemical_list": "D000970:Antineoplastic Agents; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D007633:Keratins", "country": "Germany", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0344-0338", "issue": "212(1)", "journal": "Pathology, research and practice", "keywords": "Aberrant cytokeratin expression; GISTs; Imatinib-resistance; Immunephenotype; Therapy-induced changes", "medline_ta": "Pathol Res Pract", "mesh_terms": "D000970:Antineoplastic Agents; D015820:Cadherins; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D007633:Keratins; D008875:Middle Aged; D010641:Phenotype; D047428:Protein Kinase Inhibitors", "nlm_unique_id": "7806109", "other_id": null, "pages": "63-7", "pmc": null, "pmid": "26616113", "pubdate": "2016-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Morphologic shift associated with aberrant cytokeratin expression in a GIST patient after tyrosine kinase inhibitors therapy. A case report with a brief review of the literature.", "title_normalized": "morphologic shift associated with aberrant cytokeratin expression in a gist patient after tyrosine kinase inhibitors therapy a case report with a brief review of the literature" }

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"1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NILOTINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, QD", "drugenddate": "201108", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal stromal tumour", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal mass", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neoplasm recurrence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Subileus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201108" } }, "primarysource": { "literaturereference": "ALESSANDRINIA L, CANZONIERIA V, GASPAROTTOB D, MIOLOC G, TORRISI E, PERINA T ET. AL.. MORPHOLOGIC SHIFT ASSOCIATED WITH ABERRANT CYTOKERATIN EXPRESSION IN A GIST PATIENT AFTER TYROSINE KINASE INHIBITORS THERAPY. A CASE REPORT WITH A BRIEF REVIEW OF THE LITERATURE. RESEARCH AND PRACTICE. 2016?212 (1):63-7", "literaturereference_normalized": "morphologic shift associated with aberrant cytokeratin expression in a gist patient after tyrosine kinase inhibitors therapy a case report with a brief review of the literature", "qualification": null, "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160122", "receivedate": "20140613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10235037, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160525" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-112520", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, 4 WEEKS ON, 2 WEEKS OFF", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NILOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugdosageform": null, "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG/ DAY WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078340", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROINTESTINAL STROMAL TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Subileus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANZONIERI V, GASPAROTTO D, ALESSANDRINI L, MIOLO G, TORRISI E, PERIN T, ET AL. MORPHOLOGIC SHIFT ASSOCIATED WITH ABERRANT CYTOKERATIN EXPRESSION IN A GIST PATIENT AFTER TYROSINE KINASE INHIBITORS THERAPY. A CASE REPORT WITH A BRIEF REVIEW OF THE LITERATURE. PATHOL-RES-PRACT. 2016?212 (1):63-67", "literaturereference_normalized": "morphologic shift associated with aberrant cytokeratin expression in a gist patient after tyrosine kinase inhibitors therapy a case report with a brief review of the literature", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20160311", "receivedate": "20160311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12171550, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "To assess clinical outcomes of patients with airway venous malformations treated with percutaneous sclerotherapy (VMPS). We highlight the role of foamed bleomycin as a less inflammatory sclerosant and the importance of collaboration between interventional radiology and otolaryngology-head and neck surgery (OHNS).\n\n\n\nRetrospective, consecutive, single-center series.\n\n\n\nSixteen airway VMPS treatment sessions were performed (5 patients). Endoscopic needle guidance was performed by OHNS. Sclerosants included ethanol and foamed bleomycin. The following data were tabulated for each patient: hospital length of stay (LOS), clinical response, and the presence/absence of airway swelling requiring prolonged intubation. Univariate analysis was performed. P < 0.05 was considered significant.\n\n\n\nThirty-one percent (5 of 16) of treatments required endoscopic guidance. Eighty-seven percent (7 of 8) of airway VMs treated with ethanol caused significant airway swelling compared to 0% (0 of 8) of airway VMs treated with bleomycin (P = 0.0004). The LOS was significantly greater for ethanol (5 ± 0.3 days) than for bleomycin (1 day, P = 0.001). Ninety-four percent (15 of 16) of airway VM treatments had at least a partial clinical response. There was no significant difference in clinical response between ethanol and bleomycin (P = 0.30).\n\n\n\nEndoscopic and image-guided needle placement may be necessary to treat deep airway VMs. Bleomycin may cause less significant airway swelling than ethanol. This may reduce hospital LOS and prolonged intubation. Our results should be interpreted with caution because this is a very small retrospective study. Additional investigation is needed to establish safety and efficacy of foamed bleomycin.\n\n\n\n4. Laryngoscope, 126:2726-2732, 2016.", "affiliations": "Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.;Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.", "authors": "Azene|Ezana|E|;Mitchell|Sally|S|;Radvany|Martin|M|;Agrawal|Nishant|N|;Eisele|David|D|;Weiss|Clifford|C|", "chemical_list": "D001761:Bleomycin", "country": "United States", "delete": false, "doi": "10.1002/lary.26077", "fulltext": null, "fulltext_license": null, "issn_linking": "0023-852X", "issue": "126(12)", "journal": "The Laryngoscope", "keywords": "Vascular anomaly; bleomycin; percutaneous sclerotherapy; venous malformation", "medline_ta": "Laryngoscope", "mesh_terms": "D000328:Adult; D000704:Analysis of Variance; D001761:Bleomycin; D002648:Child; D005260:Female; D006801:Humans; D007400:Interprofessional Relations; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010348:Patient Care Team; D012189:Retrospective Studies; D015911:Sclerotherapy; D054079:Vascular Malformations", "nlm_unique_id": "8607378", "other_id": null, "pages": "2726-2732", "pmc": null, "pmid": "27437862", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Foamed bleomycin sclerosis of airway venous malformations: The role of interspecialty collaboration.", "title_normalized": "foamed bleomycin sclerosis of airway venous malformations the role of interspecialty collaboration" }

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FOAMED BLEOMYCIN SCLEROSIS OF AIRWAY VENOUS MALFORMATIONS: THE ROLE OF INTERSPECIALTY COLLABORATION. 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FOAMED BLEOMYCIN SCLEROSIS OF AIRWAY VENOUS MALFORMATIONS: THE ROLE OF INTERSPECIALTY COLLABORATION. 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{ "abstract": "Mechanical thrombectomy is a procedure used for the treatment of acute ischemic stroke in patients with large vessel occlusions. Usually with a low complication rate, we present a case with a complication post-thrombectomy not previously described in the literature noted on imaging as \"blooming artifact\".", "affiliations": "Tidelands Health Myrtle Beach South Carolina.;University of South Carolina School of Medicine Columbia South Carolina.;Scripps Mercy San Diego California.;University of South Carolina School of Medicine Columbia South Carolina.", "authors": "Coward|John|J|;Prier|Jillian|J|https://orcid.org/0000-0002-5943-1345;Duda|Julian|J|;Yallapragada|Anil|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2753", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2753\nCCR32753\nCase Report\nCase Reports\nPost‐thrombectomy intracranial blooming artifact\nCOWARD et al.Coward John \n1\n Prier Jillian https://orcid.org/0000-0002-5943-1345\n2\n\n3\[email protected] Duda Julian \n4\n Yallapragada Anil \n2\n\n3\n \n1 \nTidelands Health\nMyrtle Beach\nSouth Carolina\n\n\n2 \nUniversity of South Carolina School of Medicine\nColumbia\nSouth Carolina\n\n\n3 \nPRISMA Health Richland\nColumbia\nSouth Carolina\n\n\n4 \nScripps Mercy\nSan Diego\nCalifornia\n\n* Correspondence\n\nJillian Prier, PRISMA Health Richland, Department of Neurology, 8 Medical Park Dr., Suite 420, Columbia, SC, 29203.\n\nEmail: [email protected]\n\n02 6 2020 \n8 2020 \n8 8 10.1002/ccr3.v8.81361 1364\n10 8 2019 05 1 2020 24 1 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nMechanical thrombectomy is a procedure used for the treatment of acute ischemic stroke in patients with large vessel occlusions. Usually with a low complication rate, we present a case with a complication post‐thrombectomy not previously described in the literature noted on imaging as “blooming artifact”.\n\nMechanical thrombectomy is a procedure used for the treatment of acute ischemic stroke in patients with large vessel occlusions. Usually with a low complication rate, we present a case with a complication post‐thrombectomy not previously described in the literature noted on imaging as “blooming artifact”.\n\n\nartifactbloomingstrokethrombectomy source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:28.08.2020\n\n\nCoward \nJ \n, \nPrier \nJ \n, \nDuda \nJ \n, \nYallapragada \nA \n. Post‐thrombectomy intracranial blooming artifact\n. Clin Case Rep . 2020 ;8 :1361 –1364\n. 10.1002/ccr3.2753\n==== Body\n1 INTRODUCTION\nMechanical thrombectomy is a recanalization procedure used standardly for the treatment of acute ischemic stroke patients with large vessel occlusions. Complications from this procedure are uncommon. Those that have been reported are symptomatic intracranial hemorrhage within 36 hours, subarachnoid hemorrhage (SAH), air emboli, vessel dissection, major groin complications, and emboli to new vascular territories.1, 2, 3\n\n\nWe present a case of a patient who received mechanical thrombectomy, and on post procedure imaging was found to have artifact suggestive of a retained stent retriever or catheter remnant.\n\n2 CASE REPORT\nThe patient is a 24‐year‐old G3P0020 at 27 weeks’ gestation who presented to an outside hospital with acute onset of right‐sided face, arm and leg weakness with expressive aphasia and a NIHSS of 14. She was treated with IV tPA and then transported to our institution for mechanical thrombectomy. Upon arrival, her NIHSS remained 14 with a clinical syndrome consistent with a left MCA distribution stroke.\n\nOn examination, the patient was in distress with a remarkable expressive aphasia. She was able to follow commands but had difficulties in both naming and repetition. She had significant right facial weakness and right arm more than right leg weakness. There was normal left‐sided function, no neglect, no visual field defects, and no ataxia on examination.\n\nThe patient was immediately taken for repeat head Computed Tomography (CT), which did not show any acute ischemic changes or hemorrhagic conversion. A Computed Tomography Angiography (CTA) of the head and neck was then performed, which showed a complete occlusion in the left M1 segment (Figure 1). The CT perfusion demonstrated a large area of penumbra and relatively small core infarct. The RAPID software on perfusion predicted a cerebral blood flow (core) of 34.2 mL and perfusion (Tmax > 6.0 seconds) volume of 77.1 mL. The mismatch volume was estimated at 42.9 mL with a mismatch ratio of 2.3 (Figure 2).\n\nFigure 1 CTA showing left M1 occlusion 1/9/17\n\nFigure 2 CT Perfusion using iSchemaView RAPID Software 1/9/17\n\nThe patient was taken for mechanical thrombectomy. Three passes were initially attempted to retrieve the thrombus using the Solitaire™ 6 × 20 stent retrieval device without success. On the fourth pass, a 3 Max catheter was then inserted in a coaxial fashion and successfully aspirated the thrombus. A 68 catheter was also utilized in this procedure; however, it was unable to advance beyond the base of the carotid siphon and, therefore, did not take part in the aspiration. Follow‐up arteriogram demonstrated Thrombolysis in Cerebral Infarction Score (TICI) 3 with complete reperfusion (Figure 3).\n\nFigure 3 Cerebral Angiogram showing TICI 3 reperfusion post‐thrombectomy 1/9/17\n\nA follow‐up MRI the following day showed mild mass effect in the left lateral ventricle without hydrocephalus or significant midline shift. A susceptibility artifact in the left insular cortex adjacent to the site of the thrombus was identified to be a “Blooming artifact” (Figure 4). By the time the MRI was performed and the artifact was discovered, the devices used during the procedure were already discarded. It was too late to look at the devices themselves and see if there was anything missing. The Blooming artifact was visualizable in sagittal, coronal, and axial views in all sequences, including but not limited to DWI, AVC, FLAIR, and GRE. A CT scan was also performed, on which the Blooming artifact was not visualizable.\n\nFigure 4 Axial, T2 tirm‐tra‐dark fluid MR Brain without contrast showing Blooming Artifact 1/10/17\n\nThe patient improved to a NIHSS of 10 after 24 hours. A hypercoagulable panel was performed and found Factor V Leiden negative, protein S normal, protein C low, PT/PTT test normal, dilute Russell viper venom test (DRVVT) negative for antiphospholipid inhibitor, and factor VIII high. A transesophageal echocardiogram showed a small patent foramen ovale (PFO). Given her small PFO and new stroke, an ultrasound of the legs was obtained. This did not show any evidence of deep venous thrombosis. The stroke was still deemed cryptogenic, with a possible etiology of cardio‐embolic given her PFO.\n\nWe obtained an additional MRI of the brain on hospital day five to better characterize the artifact. The study again showed an identical picture of the previous MRI with a circular, blooming artifact in the left MCA distribution. We felt this was a metallic artifact from the catheter device. As a result, the patient was placed on dual antiplatelet therapy (DAPT).\n\nThe patient continued to improve with inpatient rehabilitation. She gained significant improvement in language and was able to walk with only mild assistance after 1 week. She was discharged home, on DAPT, with home health physical therapy after 8 days. Her NIHSS on discharge was 3.\n\nThe patient was discharged on hospital day sixteen and instructed to follow‐up in 4‐6 weeks. Prior to outpatient follow‐up, she delivered, at 39 weeks and 1 day gestation, a healthy female infant at 1034 g with APGAR scores of 8 and 9. She showed improved symptoms on follow‐up with mild aphasia and drift for an NIHSS of 2. A follow‐up CT angiogram showed patent anterior, middle, and posterior cerebral arteries with no flow‐limiting stenoses evident. No transcranial doppler was performed. Additional MRI continued to demonstrate the artifact, and the decision was made to keep her DAPT. Six months later, DAPT was discontinued, due to bruising, in favor of single aspirin 81mg for global stroke secondary prevention.\n\n3 DISCUSSION\nCatheter remnants after mechanical thrombectomy are a complication that has not been reported in the literature for stroke. Interestingly, catheter remnants are a rare, but reported complication of coronary catheterization and angioplasty, as well as endovascular treatment of intracranial aneurysms.4, 5 On MRI, a paramagnetic material produces a susceptibility artifact known as a “Blooming” artifact due to the interference generated in the magnetic fields. This could be due to a catheter remnant, hemosiderin from a previous hemorrhage, or gas from an air embolism.6, 7, 8 We deemed nothing else possible given the nature of the procedure.\n\nThe complication rate in acute neuro‐endovascular thrombectomy procedures is uncommon and felt to be an acceptable risk given the proven benefits. In a 2016 study of 176 patients, there were complications in 20 of 176 patients (11%). A total of 23 different adverse events were reported including sICH 8 of 176 (5%), emboli to new vascular territories 4 of 176 (2%), dissection 3 of 176 (2%), vasospasm 5 of 176 (3%), stent dislocation in 1 of 42 (2%), and stent occlusion in 2 of 42 (5%).9\n\n\nIn the SWIFT trial data, 18 of 144 (12.5%) patients had complications including symptomatic intracranial hemorrhage (4.9%), air emboli (1.4%), vessel dissection (4.2%), major groin complications (2.8%), and emboli to new vascular territories (0.7%).10\n\n\nComparing the Merci with the Solitaire FR retrieval device, the main complications were symptomatic cerebral hemorrhage (10.9% vs 1.1%; P = .013); symptomatic SAH (7.3% vs 1.1%; P = .07), air emboli (1.8% vs 1.1%; P = 1.0), emboli to new vascular territories (1.8% vs 0%; P = .38), vessel dissection (1.8% vs 4.5%; P = .65), and major groin complications (3.6% vs 7.9%; P = .48). Angiographic vasospasm was common but without clinical sequelae.10\n\n\nAccording to the 2019 update of the AHA guidelines for early management of patients with acute ischemic stroke, the first attempt was made with the stent retriever based on level 1A evidence. However, for subsequent cases the choice of aspiration vs. stent retrieval device should be made based on the comfort and/or expertise of the performing proceduralist. Given the rarity of the complication, it should not alter practice in how endovascular recanalization of acute stroke is performed.11\n\n\nWe present a novel complication in this case as we suspect this “Blooming” artifact seen on MRI was in fact a catheter remnant. Unless otherwise contraindicated, MRI is frequently performed as part of the ongoing stroke work‐up to understand both the degree of injury, pathophysiology, and mechanism of the stroke. If a Blooming artifact is present, this should raise suspicion of a possible catheter remnant and subsequent antiplatelet therapy.\n\nAs we were unable to find many reported cases of this complication, we did not have good quality of evidence on how to manage this patient. The question presented was as follows: should she be placed on dual antiplatelets for a short period of time the transition into monotherapy or should she stay on DAPT lifelong?\n\nSome anecdotal evidenced‐based guidance can be inferred from the cardiac literature where catheter remnants are a reported complication in as many as 1% of cases of percutaneous coronary interventions (PCI). Endovascular retrieval of the entrapped remnants is the preferred option; however, this is not always possible and repeated failed attempts carry the risk of perioperative complications, such as vessel perforation. Conservative medical management with DAPT can be indicated if the patient remains asymptomatic, but patients experiencing ischemia due to thrombosis of the catheter remnants require emergency coronary artery bypass grafting.4 Unfortunately, unlike PCI, bypass grafting is not an available salvage option for failed medical management of intracranial catheter remnants.\n\n4 CONCLUSION\nMuch like the presence of a bare‐metal endovascular stent within the cerebral vasculature, catheter fragments can be viewed clinically as a foreign body, representing a risk for future ischemic events if not managed appropriately. It is the opinion of the authors that medical management should include DAPT with aspirin and clopidogrel, as long as the catheter fragments are present. We will continue to monitor with follow‐up imaging.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nJohn Coward: served as a member of medical team for the case and primary author of the case report. Jillian Prier: served as a secondary author and primary editor of the case report. Julian Duda: served as a senior resident of the medical team for the case. Anil Yallapragada: served as attending physician for the case.\n\nACKNOWLEDGMENTS\nSouvik Sen, MD, MS, MPH, University of South Carolina School of Medicine, PRISMA Health Richland\n==== Refs\nREFERENCES\n1 \n\nMcCarthy \nDJ \n, \nDiaz \nA \n, \nSheinberg \nDL \n, et al. Long‐term outcomes of mechanical thrombectomy for stroke: a meta‐analysis\n. Sci World J . 2019 ;2019 :1 ‐9\n.\n2 \n\nSaver \nJL \n, \nGoyal \nM \n, \nBonafe \nA \n, et al. Stent‐retriever thrombectomy after intravenous t‐PA vs. t‐PA alone in stroke\n. N Engl J Med . 2015 ;372 (24 ):2285 ‐2295\n.25882376 \n3 \n\nMeltzer \nA \n, \nSiracuse \nJJ \n, \nParrack \nI \n, \nHuang \nZ \n, \nGill \nH \n. Complications of the endovascular management of acute ischemic stroke\n. Vasc Health Risk Manag . 2014 ;10 :675 ‐681\n.25506222 \n4 \n\nVentosa‐Fernandez \nG \n, \nMoscoso \nB \n, \nCartañá \nR \n, \nPereda \nD \n. Surgical rescue after left anterior descending catheter entrapment causing cardiogenic shock\n. Interact Cardiovasc Thorac Surg . 2016 ;24 (1 ):140 ‐142\n.27624352 \n5 \n\nYasuda \nR \n, \nMaeda \nM \n, \nUmino \nM \n, et al. Suspected metallic embolism following endovascular treatment of intracranial aneurysms\n. Am J Neuroradiol . 2016 ;37 (9 ):1696 ‐1699\n.27102315 \n6 \n\nGreenberg \nSM \n, \nVernooij \nMW \n, \nCordonnier \nC \n, et al. Cerebral microbleeds: a guide to detection and interpretation\n. Lancet Neurol . 2009 ;8 (2 ):165 ‐174\n.19161908 \n7 \n\nHwang \nY \n, \nKim \nY‐J \n. Retrograde cerebral venous air embolism on susceptibility‐weighted imaging\n. Can J Neurol Sci . 2018 ;45 (4 ):464 ‐465\n.29747705 \n8 \n\nYan \nS \n, \nChen \nQ \n, \nZhang \nX \n, et al. Extensive blooming artifact predicts no recanalization after intravenous thrombolysis\n. Eur J Neurol . 2015 ;23 (4 ):737 ‐743\n.26706832 \n9 \n\nBehme \nD \n, \nGondecki \nL \n, \nFiethen \nS \n, \nKowoll \nA \n, \nMpotsaris \nA \n, \nWeber \nW \n. Complications of mechanical thrombectomy for acute ischemic stroke—a retrospective single‐center study of 176 consecutive cases\n. Neuroradiology . 2014 ;56 (6 ):467 ‐476\n.24668181 \n10 \n\nAkins \nPT \n, \nAmar \nAP \n, \nPakbaz \nRS \n, \nFields \nJD \n. Complications of endovascular treatment for acute stroke in the SWIFT trial with solitaire and Merci devices\n. Am J Neuroradiol . 2013 ;35 (3 ):524 ‐528\n.24029392 \n11 \n\nPowers \nWJ \n, \nRabinstein \nAA \n, \nAckerson \nT \n, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association\n. Stroke . 2019 ;50 (12 ):e1 ‐e75\n.\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2050-0904", "issue": "8(8)", "journal": "Clinical case reports", "keywords": "artifact; blooming; stroke; thrombectomy", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "1361-1364", "pmc": null, "pmid": "32884754", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": "25882376;29747705;27102315;24029392;19161908;26706832;27624352;25506222;31662037;24668181", "title": "Post-thrombectomy intracranial blooming artifact.", "title_normalized": "post thrombectomy intracranial blooming artifact" }

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{ "abstract": "The most common presentations of nontuberculous mycobacterial infections in kidney transplant recipients (KTR) are cutaneous and disseminated diseases. Pleuropulmonary infection not associated with disseminated disease is rare. Its diagnosis can be difficult, requiring a combination of clinical, radiological, and bacteriological criteria. We report on a Mycobacterium avium complex pulmonary infection in a KTR with underlying chronic obstructive pulmonary disease. Chest computed tomography showed an excavated lesion of the right upper lobe, similar to a typical lesion of pulmonary tuberculosis. Evolution was favorable with multiple-drug therapy including rifampicin, ethambutol, and clarithromycin, along with a slight reduction in immunosuppression. We review the literature and discuss the epidemiology, diagnosis, management, and follow-up of this uncommon post-transplant complication.", "affiliations": "Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Medical School, Brussels, Belgium.", "authors": "Ho|T A|TA|;Rommelaere|M|M|;Coche|E|E|;Yombi|J-C|JC|;Kanaan|N|N|", "chemical_list": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D007166:Immunosuppressive Agents; D017291:Clarithromycin", "country": "Denmark", "delete": false, "doi": "10.1111/j.1399-3062.2009.00473.x", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "12(2)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": null, "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D017291:Clarithromycin; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009162:Mycobacterium avium; D009894:Opportunistic Infections; D011183:Postoperative Complications; D013183:Sputum; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary", "nlm_unique_id": "100883688", "other_id": null, "pages": "138-42", "pmc": null, "pmid": "19929882", "pubdate": "2010-04", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Nontuberculous mycobacterial pulmonary infection in renal transplant recipients.", "title_normalized": "nontuberculous mycobacterial pulmonary infection in renal transplant recipients" }

[ { "companynumb": "BE-PFIZER INC-2016149718", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "011153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mycobacterium avium complex infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atypical mycobacterial lower respiratory tract infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HO, T.. NONTUBERCULOUS MYCOBACTERIAL PULMONARY INFECTION IN RENAL TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2010;12 (2):138-142", "literaturereference_normalized": "nontuberculous mycobacterial pulmonary infection in renal transplant recipients", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160422", "receivedate": "20160314", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12179272, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "Management of frequent epileptic seizures in febrile infection-related epilepsy (FIRES) is often challenging. FIRES is an uncommon disease condition. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes. However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES. We present the case of a previously healthy 3-year-old male with new-onset status epilepticus (SE) admitted to the paediatric intensive care unit for 55 days. Despite treatment with multiple anti-epileptic agents in addition to IV anaesthetics, the patient remained in SRSE and continued to have generalised epileptic activity on electroencephalography (EEG). KD therapy was initiated on the 14th day of the onset, and the patient achieved complete neurological recovery following the KD. Throughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. The convulsions were well controlled after discharge. We discuss the treatment strategies for FIRES and highlight the role of KD therapy in the acute phase to control disease progression and improve the prognosis, and early diagnosis of FIRES and early initiation of KD therapy combined with anti-epileptic drugs (AEDs) could improve the prognosis.", "affiliations": "Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.;Department of Emergency, Children's Hospital of Nanjing Medical University, Nanjing, China.", "authors": "Li|Wen-Jing|WJ|;Xue|Chun-Ling|CL|;Zhang|Yong|Y|;Wu|Li-Hui|LH|;Chen|Dong-Mei|DM|;Chen|Feng|F|;Xu|Jing|J|;Li|Zhuo|Z|;Miao|Hong-Jun|HJ|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/tp-21-121", "fulltext": "\n==== Front\nTransl Pediatr\nTransl Pediatr\nTP\nTranslational Pediatrics\n2224-4336\n2224-4344\nAME Publishing Company\n\n34733679\ntp-10-09-2392\n10.21037/tp-21-121\nCase Report\nKetogenic diet (KD) therapy in the acute phase of febrile infection-related epilepsy syndrome (FIRES): a case report\nLi Wen-Jing 1 ^\nXue Chun-Ling 2\nZhang Yong 1\nWu Li-Hui 2\nChen Dong-Mei 2\nChen Feng 1\nXu Jing 1\nLi Zhuo 2\nMiao Hong-Jun 2\n1 Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China;\n2 Department of Emergency, Children’s Hospital of Nanjing Medical University, Nanjing, China\nCorrespondence to: Zhuo Li; Hong-Jun Miao. Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China. Email: [email protected]; [email protected].\n^ ORCID: 0000-0003-1684-4390.\n\n9 2021\n9 2021\n10 9 23922397\n25 3 2021\n29 6 2021\n2021 Translational Pediatrics. All rights reserved.\n2021\nTranslational Pediatrics.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nManagement of frequent epileptic seizures in febrile infection-related epilepsy (FIRES) is often challenging. FIRES is an uncommon disease condition. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes. However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES. We present the case of a previously healthy 3-year-old male with new-onset status epilepticus (SE) admitted to the paediatric intensive care unit for 55 days. Despite treatment with multiple anti-epileptic agents in addition to IV anaesthetics, the patient remained in SRSE and continued to have generalised epileptic activity on electroencephalography (EEG). KD therapy was initiated on the 14th day of the onset, and the patient achieved complete neurological recovery following the KD. Throughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. The convulsions were well controlled after discharge. We discuss the treatment strategies for FIRES and highlight the role of KD therapy in the acute phase to control disease progression and improve the prognosis, and early diagnosis of FIRES and early initiation of KD therapy combined with anti-epileptic drugs (AEDs) could improve the prognosis.\n\nKeywords:\n\nFebrile infection-related epilepsy syndrome (FIRES)\nstatus epilepticus (SE)\nketogenic diet (KD)\nacute phase\ncase report\n==== Body\npmcIntroduction\n\nFebrile infection-related epilepsy syndrome (FIRES) describes an acute-onset, potentially fatal epileptic encephalopathy that develops in previously healthy children and adolescents during or soon after afebrile episode or any other infectious disease. Children with FIRES develop refractory epilepsy with severe cognitive deficits that affect the function of the temporal and frontal lobes (1). The annual incidence of FIRES among children and adolescents is 1:1,000,000 and 1:100,000, respectively (2). FIRES mainly affects children aged 3–15 years old (3), with a peak during school age and male predominance (4).\n\nThe proposed consensus definition of 2018 identifies FIRES as a subcategory of new-onset refractory status epilepticus (NORSE) (5), with a history of febrile infection, a history of fever between 2 weeks and 24 h prior to the onset of refractory status epilepticus (SE), and the seizure during the epileptic episode is often refractory to drugs. The pathogenesis underlying FIRES is still a matter of debate, and the clinical outcome of FIRES is poor (2).\n\nThe most important treatment for FIRES is the control of epileptic seizures, especially during the acute phase (6). Although general expert consensus in the literature recommends the administration of anti-epileptic drugs (AEDs) or anticonvulsants, they are ineffective in most cases of FIRES (7). However, better seizure control during the acute stage of FIRES could protect against injury to the nervous system. Ketogenic diet (KD) can effectively resolve super-refractory status epilepticus (SRSE) in the acute phase and improve the prognosis of FIRES.\n\nHerein, we report the case of a 3-year-old boy with FIRES, in whom we focused on KD therapy in the acute phase and ultimately achieved complete neurological recovery after extensive treatment.\n\nCase presentation\n\nClinical data\n\nA 3-year-old boy with normal development and no other symptoms of metabolic disease had an onset of intermittent fever for 11 days, which quickly progressed to seizures.\n\nHis vital signs included a temperature of 38.5 °C, blood pressure of 112/72 mmHg, a pulse of 153 beats per minute, and a respiratory rate of 20 breaths per minute. A venous blood gas analysis showed a sodium level of 129 mmol/L, potassium 4.3 mmol/L, and pH 7.33. The results of the investigations revealed a white blood cell (WBC) count of 14.12×109/L (reference range 4×109–10×109/L), chest X-ray films revealed dense flocculent shadow in both the lungs, electroencephalography (EEG) revealed a generalised background slowing and frequent right-sided electrical activity, magnetic resonance imaging (MRI) showed clear atrophy, and a lumbar puncture followed by an analysis of the cerebrospinal fluid showed normal results. Based on these, the diagnosis was central nervous system infection, viral encephalitis, SE, and bronchopneumonia.\n\nTreatment\n\nAnti-infectives, anti-epileptics, and relevant symptomatic treatment were administered.\n\nAnti-infective therapy\n\nGiven the risk of the possibility of co-infection with bacteria, viruses, and mycoplasma, the patient was immediately initiated on anti-infective therapy.\n\nThe patient was treated empirically with cefodizime following admission to our pediatric intensive care unit, considering his body temperature of 38.5 °C and WBC count of 14.12×109/L. However, he continued to have a recurrent fever with a higher thermal peak than before, and cefodizime was changed to meropenem. Due to the drug-drug interactions between meropenem and anti-epileptic agents affecting seizure control, ceftazidime was resumed again when the infection was better controlled following three consecutive routine blood examinations. Ceftazidime was discontinued once the results of the routine blood tests showed a return to normal values, and no abnormalities were found on chest radiography after 2 weeks of treatment. However, his fever recurred 3 days later with a febrile peak of 38.5 °C. The results of routine blood examination showed C-reactive protein (CRP) of 18 mg/L, WBC count of 19.65×109/L, and 0.991 ng/mL of procalcitonin (PCT), and the sputum culture identified Burkholderia cepacia. Based on the results of the drug susceptibility test, it was decided to administer meropenem. After a 5-day treatment, meropenem was changed to ceftazidime when the results of the blood culture were negative for Burkholderia cepacia but showed sensitivity to ceftazidime. Anti-infective treatment was intensified by the addition of sulfamethoxazole tablets because the tracheal intubation culture was positive for Burkholderia cepacia and Staphylococcus aureus, and the CRP level and WBC counts were higher than before. After treatment with ceftazidime and compound sulfamethoxazole tablets for 3 weeks, the patient was discharged when his health was in better condition.\n\nDrug selection and dose adjustment were tailored according to the clinical manifestations, indicators of infection, and results of the culture. The anti-infective treatment regimen is listed in (Table 1), and the indicators of infections and body temperature during the anti-infective therapy are shown in (Figure 1).\n\nTable 1 Anti-infective treatment regimen of the patient during hospitalization\n\nDate\tDrugs\tDosage\tEtiological examination\tComments\t\n9.15–9.17\tCefodizime\t0.6 g, bid, ivgtt\t–\tExperiential therapy\t\n9.18–9.24\tMeropenem\t0.3 g, q8h, ivgtt\t–\tInfection aggravated\t\n9.25–10.4\tCeftazidime\t0.75 g, q12h, ivgtt\t–\tEffective control of infection\t\n10.5–10.8\tAzithromycin\t0.125 g, qd, po\tHaemophilus influenza (+)\tSputum culture\t\n10.11–10.15\tMeropenem\t0.25 g, q8h, ivgtt\tBurkholderia cepacia (+)\tSputum culture\t\n10.16–10.27\tCeftazidime\t0.625 g, q12h, ivgtt\tBurkholderia cepacia (+)\tSputum culture\t\n10.28–11.14\tCeftazidime\t0.625 g, q12h, ivgtt\tBurkholderia cepacia (+)\tTracheal intubation culture\t\nSulfamethoxazole\t0.24 g, q12h, po\tStaphylococcus aureus (+)\tInfection aggravated\t\n\nFigure 1 The infectious indicators and body temperature of the patient during hospitalization. CRP, C-reactive protein; WBC, white blood cell; PCT, procalcitonin.\n\nThe patient was treated with acyclovir and voriconazole for 3 weeks because he tested positive for Epstein-Barr (EB) virus and a fungus, and erythromycin for 2 weeks because he tested positive for Mycoplasma pneumoniae IgG.\n\nAnti-epileptic therapy\n\nDespite broad-spectrum AED therapies (topiramate, levetiracetam, phenytoin sodium, and clonazepam), the patient had frequent epileptic seizures, especially tonic-clonic seizures. A midazolam infusion was initiated and up-titrated to 0.3 mg kg−1 h−1; however, it failed to achieve burst suppression, and the patient continued to have generalised epileptic activity on EEG.\n\nWhile these agents were being titrated, KD therapy was initiated on the 14th day of the onset, and screening for hematuria and B-scan examination of the hepatobiliary tree, pancreas, and spleen were performed before initiating KD therapy.\n\nThe classic KD calculates the ratio of grams of fat to grams of carbohydrates plus protein. The most feasible ratios calculated to date are 3:1 or 4:1, with approximately 80%–90% of the energy provided by fats and 10% by carbohydrates and proteins collectively (8). The patient received enteral KD (EN KD) consisting of a commercially available ketogenic formula (KD milk powder) and a commercially available fat emulsion with medium-chain triglycerides (Peptamen Junior). His body temperature was stable, and the seizure frequency, seizure type, and intervals between the seizures were significantly improved after approximately 1-month of KD therapy. The formula for KD therapy and the corresponding outcome are listed in (Table 2).\n\nTable 2 The formula of KD therapy and the improving symptom of seizure\n\nDate\tSeizure frequency\tSeizure\ntypes\tGrand mal\tRelief time of seizure\tFormula of KD (q3h)\t\nKD milk powder (g)\tPeptamen Junior (g)\tWater (mL)\t\n9.15–9.27\tContinuous\ta\t√\t1–5 min\t–\t–\t–\t\n9.28\tContinuous\ta\t√\t1–5 min\t6.8\t0.5\t50\t\n9.29\tContinuous\ta\t√\t1–5 min\t13.5\t1.0\t70\t\n9.30–10.4\tContinuous\tb\t–\t1–3 min\t13.5\t1.0\t70\t\n10.5–10.7\tContinuous\tb\t–\t1–3 min\t14.0\t0.4\t70\t\n10.8–10.11\tParoxysmal\tc\t–\t1–2 min\t14.0\t0.4\t70\t\n10.12–10.17\tParoxysmal\tc\t–\t1–2 min\t15.5\t–\t80\t\n10.18–10.20\tParoxysmal\tc\t–\t1–2 min\t16.5\t–\t80\t\n10.21–10.22\tParoxysmal\td\t–\t30 s\t16.5\t–\t80\t\n10.23–10.27\tOccasional\td\t–\t30 s\t16.0\t2.3\t80\t\n10.28\tOccasional\td\t–\t30 s\t11.0\t11.0\t90\t\n10.29–10.30\tOccasional\td\t–\t15 s\t–\t22.0\t90\t\n10.31–11.5\tOccasional\te\t–\t15 s\t–\t–\t–\t\n11.6–11.14\t–\t–\t–\t–\t–\t–\t–\t\na, visible generalised convulsions, elevated muscle tone, and dribbling at the mouth; b, rhythmic muscle twitches, elevated muscle tone, and tonic eye deviation; c, rhythmic muscle twitches, twitching in the face and nystagmoid, or rhythmic eye movements; d, Elevated muscle tone, gazed in both eyes and skewed angles of the mouth; e, rhythmic muscle twitches and dribbling at the mouth. KD, ketogenic diet.\n\nDuring the KD therapy, electrolytes, arterial blood gases, serum ketone bodies, and glucose were monitored, and these indicators were checked again once the blood ketone level was above 5.5 mmol/L or the blood glucose level was below 2.5 mmol/L. There were no symptoms of hypoglycaemia or hyper ketoacidosis with blood ketone level of 1.2–4.9 mmol/L and blood glucose 2.7–7.9 mmol/L.\n\nRelevant symptomatic treatment\n\nThe patient was administered mannitol and glycerol fructose alternately to reduce the intracranial pressure, and the dosage and frequency were gradually reduced according to the clinical status during the treatment. The combination of dextro-ibuprofen suppository with physical cooling was effective in reducing the body temperature with recurrent fever during the course of the disease.\n\nPrognosis\n\nThroughout the remainder of admission, the patient was successfully weaned off the ventilator, tolerated oral meals, and worked with occupational and physical therapists to return to his baseline functional status. He was continued on topiramate, levetiracetam, phenytoin sodium, and clonazepam and was ultimately discharged on the AED regimen.\n\nThe patient continued rehabilitation after discharge from the hospital. Follow-up visits were made 1 to 2 months after discharge and the convulsions were well controlled; however, the patient was lost to follow-up 6 months after discharge.\n\nDiscussion\n\nWe present a case of a rare epilepsy syndrome with unclear aetiology in a healthy boy who ultimately recovered completely after extensive treatment, especially KD therapy, during the acute phase. The clinical outcome warrants discussion as FIRES is typically considered a life-threatening condition with mortality up to 30% and intellectual disability in 66–100% of the survivors (9,10).\n\nSince there are no known causes, and no disease markers or genetic testing are available for the diagnosis, FIRES is typically diagnosed at a late stage in the clinical course (4), which is primarily based on the clinical status in children with preceding fever who develop refractory SE after known causes of SE have been excluded (9).\n\nIn this particular case of FIRES, none of the anti-epileptic therapeutic approaches appeared to be significantly effective, with the exception of KD.\n\nKD contains high fat content, low carbohydrate content, and adequate protein content. It alters the primary cerebral energy supply from glucose to ketone bodies, mimicking biochemical changes during starvation (11,12). KD is the most effective when taken after fasting or when the body’s calorie levels are low. This is because the brain normally uses glucose as a source of energy rather than fats. However, glucose levels are low in the fasting state; thus, the brain utilises fats as the source of energy in such circumstances (13). Although the exact mechanisms underlying the anticonvulsive activity of KD are still unclear, it is thought that KD has anti-epileptic activity, anti-inflammatory effects, and neuroprotective activity (14-17), making it a non-pharmacological substitute for the treatment of epilepsy. Several recent studies have indicated that KD is not only suitable for acute phase therapy but also long-term disease management (18,19). In addition to traditional AEDs, early KD treatment was helpful for both seizure control and cognitive outcome after FIRES (20,21).\n\nConclusions\n\nIn summary, this challenging case of FIRES in a previously healthy boy emphasises the importance of early initiation of KD in the acute phase. Despite the high risk of mortality and the difficulty in controlling frequent epileptic seizures, clinical outcome resulted in complete neurological recovery. This case also showed that KD was an effective therapeutic option for FIRES, and early diagnosis of FIRES and early initiation of KD therapy combined with AEDs could improve the prognosis.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tp-21-121 10.21037/tp-21-121 10.21037/tp-21-121\n\nAcknowledgments\n\nFunding: None.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at https://dx.doi.org/10.21037/tp-21-121\n\nPeer Review File: Available at https://dx.doi.org/10.21037/tp-21-121\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tp-21-121). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Kramer U Chi CS Lin KL Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia 2011;52 :1956-65. 10.1111/j.1528-1167.2011.03250.x 21883180\n2 van Baalen A Häusler M Plecko-Startinig B Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012;43 :209-16. 10.1055/s-0032-1323848 22911482\n3 van Baalen A Vezzani A Häusler M Febrile Infection-Related Epilepsy Syndrome: Clinical Review and Hypotheses of Epileptogenesis. Neuropediatrics 2017;48 :5-18.27919115\n4 Gaspard N Hirsch LJ Sculier C New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia 2018;59 :745-52. 10.1111/epi.14022 29476535\n5 Hirsch LJ Gaspard N van Baalen A Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 2018;59 :739-44. 10.1111/epi.14016 29399791\n6 Serino D Santarone ME Caputo D Febrile infection-related epilepsy syndrome (FIRES): prevalence, impact and management strategies. Neuropsychiatr Dis Treat 2019;15 :1897-903. 10.2147/NDT.S177803 31371963\n7 Sculier C Gaspard N . New onset refractory status epilepticus (NORSE). Seizure 2019;68 :72-8. 10.1016/j.seizure.2018.09.018 30482654\n8 Starnes K Miller K Wong-Kisiel L A Review of Neurostimulation for Epilepsy in Pediatrics. Brain Sci 2019;9 :283. 10.3390/brainsci9100283 31635298\n9 Caraballo RH Reyes G Avaria MF Febrile infection-related epilepsy syndrome: a study of 12 patients. Seizure 2013;22 :553-9. 10.1016/j.seizure.2013.04.005 23643626\n10 Appenzeller S Helbig I Stephani U Febrile infection-related epilepsy syndrome (FIRES) is not caused by SCN1A, POLG, PCDH19 mutations or rare copy number variations. Dev Med Child Neurol 2012;54 :1144-8. 10.1111/j.1469-8749.2012.04435.x 23066759\n11 Klepper J. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 2008;49 Suppl 8 :46-9. 10.1111/j.1528-1167.2008.01833.x 19049586\n12 Yang H Wu J Guo R Glycolysis in energy metabolism during seizures. Neural Regen Res 2013;8 :1316-26.25206426\n13 Anwar H Khan QU Nadeem N Epileptic seizures. Discoveries (Craiova) 2020;8 :e110. 10.15190/d.2020.7 32577498\n14 Liu F Peng J Zhu C Efficacy of the ketogenic diet in Chinese children with Dravet syndrome: A focus on neuropsychological development. Epilepsy Behav 2019;92 :98-102. 10.1016/j.yebeh.2018.12.016 30641252\n15 Nabbout R Mazzuca M Hubert P Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51 :2033-7. 10.1111/j.1528-1167.2010.02703.x 20813015\n16 Chang P Augustin K Boddum K Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain 2016;139 :431-43. 10.1093/brain/awv325 26608744\n17 Dupuis N Curatolo N Benoist JF Ketogenic diet exhibits anti-inflammatory properties. Epilepsia 2015;56 :e95-8. 10.1111/epi.13038 26011473\n18 Singh RK Joshi SM Potter DM Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet. Pediatrics 2014;134 :e1431-5. 10.1542/peds.2013-3106 25332495\n19 Nangia S Caraballo RH Kang HC Is the ketogenic diet effective in specific epilepsy syndromes? Epilepsy Res 2012;100 :252-7. 10.1016/j.eplepsyres.2012.01.015 22424762\n20 Fox K Wells ME Tennison M Febrile Infection-Related Epilepsy Syndrome (FIRES): A Literature Review and Case Study. Neurodiagn J 2017;57 :224-33. 10.1080/21646821.2017.1355181 28898171\n21 Appavu B Vanatta L Condie J Ketogenic diet treatment for pediatric super-refractory status epilepticus. Seizure 2016;41 :62-5. 10.1016/j.seizure.2016.07.006 27475280\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2224-4336", "issue": "10(9)", "journal": "Translational pediatrics", "keywords": "Febrile infection-related epilepsy syndrome (FIRES); acute phase; case report; ketogenic diet (KD); status epilepticus (SE)", "medline_ta": "Transl Pediatr", "mesh_terms": null, "nlm_unique_id": "101649179", "other_id": null, "pages": "2392-2397", "pmc": null, "pmid": "34733679", "pubdate": "2021-09", "publication_types": "D002363:Case Reports", "references": "27919115;31371963;20813015;26011473;29476535;22911482;29399791;27475280;22424762;28898171;19049586;26608744;25206426;30641252;21883180;23066759;31635298;30482654;25332495;23643626;32577498", "title": "Ketogenic diet (KD) therapy in the acute phase of febrile infection-related epilepsy syndrome (FIRES): a case report.", "title_normalized": "ketogenic diet kd therapy in the acute phase of febrile infection related epilepsy syndrome fires a case report" }

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}, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Seizure", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYTOIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": 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Ketogenic diet (KD) therapy in the acute phase of febrile infection-related epilepsy syndrome (FIRES): A case report. Translational Pediatrics. 2021;10(9):2392-7", "literaturereference_normalized": "ketogenic diet kd therapy in the acute phase of febrile infection related epilepsy syndrome fires a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20220210", "receivedate": "20220210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20456353, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "OBJECTIVE\nTo determine the efficacy and safety of intra-cardiac lidocaine administration to induce fetal demise before second-trimester medication abortion in a teaching hospital in Addis Ababa, Ethiopia.\n\n\nMETHODS\nWe performed a retrospective chart review to collect selected sociodemographic and clinical information. All patients who received fetal intra-cardiac lidocaine between January 1, 2019 and April 30, 2019 were included in the study. Fetal demise was considered successful if achieved within 24 hours after fetal intra-cardiac lidocaine administration. We analyzed the data using SPSS version 20. We used frequency tables to describe the data and performed a multivariable analysis to determine associations between variables.\n\n\nRESULTS\nA total of 80 fetuses were given intra-cardiac lidocaine.The mean gestational age was 23+1 weeks (range 21+0 -27+5 weeks). Twenty-four hours after lidocaine administration 76 (95%) pregnancies showed negative fetal cardiac activity. Fetuses at gestational ages of 21-23+6 weeks were five times more likely to have negative cardiac activity compared with those with gestational ages between 24 and 28 weeks (P=0.001). Two women developed nausea, vomiting, and a metallic taste, but no serious adverse events were reported.\n\n\nCONCLUSIONS\nIntra-cardiac lidocaine is effective at inducing fetal demise before late second-trimester medication abortion with no associated serious adverse events or complications.", "affiliations": "Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, University of Michigan, Ann Arbor, MI, USA.;Department of Obstetrics, Gynecology and Reproductive Science, University of Vermont, Burlington, VT, USA.;Department of Obstetrics & Gynecology, Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.;Department of Obstetrics & Gynecology, University of Michigan, Ann Arbor, MI, USA.", "authors": "Tolu|Lemi Belay|LB|;Tufa|Tesfaye H|TH|;Abas|Ferid|F|;Kahn|Chavi|C|;MacAfee|Lauren|L|;Prager|Sarah|S|;Bell|Jason D|JD|", "chemical_list": "D008012:Lidocaine", "country": "United States", "delete": false, "doi": "10.1002/ijgo.13419", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-7292", "issue": "153(1)", "journal": "International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics", "keywords": "Ethiopia; Fetal demise; Intra-cardiac lidocaine; Late abortion; Lidocaine; Medication abortion", "medline_ta": "Int J Gynaecol Obstet", "mesh_terms": "D000028:Abortion, Induced; D000293:Adolescent; D000328:Adult; D005002:Ethiopia; D005260:Female; D005313:Fetal Death; D005318:Fetal Heart; D005865:Gestational Age; D006801:Humans; D008012:Lidocaine; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "0210174", "other_id": null, "pages": "125-129", "pmc": null, "pmid": "33043458", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Intra-cardiac lidocaine administration to induce fetal demise before late second-trimester abortion: Retrospective review.", "title_normalized": "intra cardiac lidocaine administration to induce fetal demise before late second trimester abortion retrospective review" }

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Intra-cardiac lidocaine administration to induce fetal demise before late second-trimester abortion: Retrospective review. 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{ "abstract": "The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored.\n\n\n\nPatients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ).\n\n\n\nBetween 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3).\n\n\n\nGastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.", "affiliations": "Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgery, Nieuwegein, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Biometrics, Amsterdam, the Netherlands.;Department of Gastrointestinal Oncology, Amsterdam, the Netherlands.;Department of Medical Oncology, St Antonius Hospital, Nieuwegein, the Netherlands.;Department of Pharmacy, Amsterdam, the Netherlands.;>Department of Clinical Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.;Department of Surgery, Nieuwegein, the Netherlands.;Department of Surgery, Nieuwegein, the Netherlands.;Department of Gastrointestinal Oncology, Amsterdam, the Netherlands.;Department of Surgical Oncology, Amsterdam, the Netherlands.", "authors": "van der Kaaij|R T|RT|;Wassenaar|E C E|ECE|;Koemans|W J|WJ|0000-0003-0101-081X;Sikorska|K|K|;Grootscholten|C|C|;Los|M|M|;Huitema|A|A|;Schellens|J H M|JHM|;Veenhof|A A F A|AAFA|;Hartemink|K J|KJ|;Aalbers|A G J|AGJ|;van Ramshorst|B|B|;Boerma|D|D|;Boot|H|H|;van Sandick|J W|JW|", "chemical_list": "D000970:Antineoplastic Agents; D000077150:Oxaliplatin; D000077143:Docetaxel", "country": "England", "delete": false, "doi": "10.1002/bjs.11588", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1323", "issue": "107(11)", "journal": "The British journal of surgery", "keywords": null, "medline_ta": "Br J Surg", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D005743:Gastrectomy; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms; D013274:Stomach Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "0372553", "other_id": null, "pages": "1520-1528", "pmc": null, "pmid": "32277764", "pubdate": "2020-10", "publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Treatment of PERItoneal disease in Stomach Cancer with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy: PERISCOPE I initial results.", "title_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results" }

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WASSENAAR E.C.E.? KOEMANS W.J.? SIKORSKA K., GROOTSCHOLTEN C., LOS M. ET AL. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. 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WASSENAAR E.C.E.? KOEMANS W.J., SIKORSKA K., GROOTSCHOLTEN C., LOS M. ET AL. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. 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TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. BRITISH JOURNAL OF SURGERY. 2020?107 (11):1520-1528", "literaturereference_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20201229", "receivedate": "20190422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16225155, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" }, { "companynumb": "NL-PFIZER INC-2019171151", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "033", "drugauthorizationnumb": "022234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, (NORMOTHERMIC DOCETAXEL (90 MINUTES))", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "033", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "460 MG/M2, (HYPERTHERMIC OXALIPLATIN (30 MINUTES),FIXED DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA GASTRIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "460", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Postoperative ileus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DER KAAIJ, R.. TREATMENT OF PERITONEAL DISEASE IN STOMACH CANCER WITH CYTOREDUCTIVE SURGERY AND HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY: PERISCOPE I INITIAL RESULTS. BRITISH JOURNAL OF SURGERY. 2020?107 (11):1520-1528", "literaturereference_normalized": "treatment of peritoneal disease in stomach cancer with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy periscope i initial results", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20201228", "receivedate": "20190422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16224983, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" } ]

{ "abstract": "Pure red cell aplasia (PRCA) is characterised by an anaemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with the selective absence of erythroid precursor cells. Drug-induced PRCA is a rare cause of secondary erythroid aplasia, but distinct from the primary and most secondary forms, it is usually acute and fully reversible upon withdrawal of the causative drug. We report a 36 year-old Chinese man who developed diphenylhydantoin associated PRCA two months after commencing the treatment. Reappearance of reticulocytes was observed six days following the cessation of diphenylhydantoin therapy and the haemoglobin level rose to normal one month later. The extreme rarity of this adverse reaction to a drug used so widely strongly suggests an individual predisposition.", "affiliations": "Department of Medicine, National University of Singapore.", "authors": "Kueh|Y K|YK|;Yeo|T C|TC|;Choo|M H|MH|", "chemical_list": "D010672:Phenytoin", "country": "Singapore", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0304-4602", "issue": "20(3)", "journal": "Annals of the Academy of Medicine, Singapore", "keywords": null, "medline_ta": "Ann Acad Med Singap", "mesh_terms": "D000328:Adult; D006801:Humans; D008297:Male; D010672:Phenytoin; D012010:Red-Cell Aplasia, Pure", "nlm_unique_id": "7503289", "other_id": null, "pages": "407-9", "pmc": null, "pmid": "1929190", "pubdate": "1991-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Reversible pure red cell aplasia associated with diphenylhydantoin therapy.", "title_normalized": "reversible pure red cell aplasia associated with diphenylhydantoin therapy" }

[ { "companynumb": "SG-PFIZER INC-2018381925", "fulfillexpeditecriteria": "1", "occurcountry": "SG", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL HAEMATOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1990", "drugstartdateformat": "602", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "THROMBOSIS PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "198904", "drugstartdateformat": "610", "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KUEH, Y.. REVERSIBLE PURE RED CELL APLASIA ASSOCIATED WITH DIPHENYLHYDANTOIN THERAPY. ANNALS OF THE ACADEMY OF MEDICINE. 1991?20(3):407?409", "literaturereference_normalized": "reversible pure red cell aplasia associated with diphenylhydantoin therapy", "qualification": "1", "reportercountry": "SG" }, "primarysourcecountry": "SG", "receiptdate": "20180928", "receivedate": "20180925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15425241, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "BACKGROUND\nThe aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage.\n\n\nMETHODS\nSixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded.\n\n\nRESULTS\nBaseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08).\n\n\nCONCLUSIONS\nAt the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.", "affiliations": "Department of Cardiac Surgery, University of Munich, Grosshadern Medical Center, Marchioninistrasse 15, 81366 Munich, Germany. [email protected]", "authors": "Meiser|Bruno M|BM|;Groetzner|Jan|J|;Kaczmarek|Ingo|I|;Landwehr|Peter|P|;Müller|Markus|M|;Jung|Sebastian|S|;Uberfuhr|Peter|P|;Fraunberger|Peter|P|;Stempfle|Hans-Ulrich|HU|;Weis|Michael|M|;Reichart|Bruno|B|", "chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1097/01.tp.0000129814.52456.25", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1337", "issue": "78(4)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases; D016572:Cyclosporine; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D006949:Hyperlipidemias; D007166:Immunosuppressive Agents; D007668:Kidney; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D016559:Tacrolimus; D017211:Treatment Failure", "nlm_unique_id": "0132144", "other_id": null, "pages": "591-8", "pmc": null, "pmid": "15446320", "pubdate": "2004-08-27", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?", "title_normalized": "tacrolimus or cyclosporine which is the better partner for mycophenolate mofetil in heart transplant recipients" }

[ { "companynumb": "DE-CONCORDIA PHARMACEUTICALS INC.-E2B_00010164", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 X 125 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "0.03 TO 0.1 MG/KG/DAY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "AS A SHORT-TERM INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELLCEPT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021959", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aspergillus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MEISER B,GROETZNER J,KACZMAREK I,LANDWEHR P,MULLER M,JUNG S. TACROLIMUS OR CYCLOSPORINE: WHICH IS THE BETTER PARTNER FOR MYCOPHENOLATE MOFETIL IN HEART TRANSPLANT RECIPIENTS?.. TRANSPLANTATION 2004 AUG 27?78 (4)::591-598.", "literaturereference_normalized": "tacrolimus or cyclosporine which is the better partner for mycophenolate mofetil in heart transplant recipients", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180228", "receivedate": "20180228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14579934, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" } ]

{ "abstract": "This study sought to report pregnancy outcomes in women following cardiac transplantation.\n\n\n\nThis was a descriptive retrospective cohort study of women with pregnancies following cardiac transplantation managed at two large tertiary centres in Canada and Belgium between 2001 and 2017.\n\n\n\nSixteen women had 17 singleton pregnancies following cardiac transplantation. The mean maternal age was 28 ± 5.8, and the transplant-to-pregnancy interval was 7.3 ± 4.0 years. There were two first trimester terminations, one for teratogenicity concerns and the other because of a maternal cardiac condition. There was one spontaneous miscarriage. All women had normal left ventricular function at the start of pregnancy. Graft rejection occurred in two women. Other maternal complications included anemia requiring blood transfusion (n = 5), renal failure or deterioration (n = 4), preeclampsia (n = 2), and urine infections (n = 2). The mean GA at delivery was 35 ± 3.5 weeks. Six infants were born preterm, and two were small-for-gestational-age. Fetal anomalies were identified in two pregnancies. Women were followed after pregnancy for a median of 5.6 years (range, 10 months to 15 years). Although there were no deaths during pregnancy, two women died at 10 and 18 months after delivery.\n\n\n\nWith appropriate multidisciplinary care, women with cardiac transplants can have successful pregnancies. Although rates of fetal loss are low, these women continue to be at risk for graft rejection, preterm birth, other pregnancy-related complications, and cardiovascular death.", "affiliations": "Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON. Electronic address: rohan.d'[email protected].;Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.;Division of Cardiology, Pregnancy and Heart Disease Program, Department of Medicine, Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON.;Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON.;Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.;Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.;Division of Cardiology, Pregnancy and Heart Disease Program, Department of Medicine, Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON.;Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON.;Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, ON.", "authors": "D'Souza|Rohan|R|;Soete|Elisabeth|E|;Silversides|Candice K|CK|;Zaffar|Nusrat|N|;Van Mieghem|Tim|T|;Van Cleemput|Johan|J|;Bhagra|Catriona|C|;Sermer|Mathew|M|;Ross|Heather|H|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jogc.2017.08.030", "fulltext": null, "fulltext_license": null, "issn_linking": "1701-2163", "issue": "40(5)", "journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC", "keywords": "Cardiac transplantation; management; outcomes; pregnancy; pregnancy complications", "medline_ta": "J Obstet Gynaecol Can", "mesh_terms": "D000328:Adult; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "101126664", "other_id": null, "pages": "566-571", "pmc": null, "pmid": "29153738", "pubdate": "2018-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Pregnancy Outcomes Following Cardiac Transplantation.", "title_normalized": "pregnancy outcomes following cardiac transplantation" }

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PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. 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PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA. 2018?40(5):566?71", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20210212", "receivedate": "20180627", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15073029, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "CA-ASTELLAS-2018US026022", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysplasia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "D^SOUZA R, SOETE E, SILVERSIDES CK, ZAFFAR N, VAN MIEGHEM T, VAN CLEEMPUT J ET AL. PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA. 2018?40(5):566-71", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20180608", "receivedate": "20180608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14987450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2018-04399", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "9 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COUMADIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "D^SOUZA R, SOETE E, SILVERSIDES CK, ZAFFAR N, ET AL. PREGNANCY OUTCOMES FOLLOWING CARDIAC TRANSPLANTATION. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA. 2018?40(5):566-571", "literaturereference_normalized": "pregnancy outcomes following cardiac transplantation", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190101", "receivedate": "20190101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15779521, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "BACKGROUND\nReports have demonstrated the superior activity of combining both irinotecan and oxaliplatin (FOLFOXIRI) therapy. An option for gaining similar benefits with less toxicity would be the administration of irinotecan through a hepatic artery approach. The aim of this study was to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis.\n\n\nMETHODS\nPatients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival.\n\n\nRESULTS\nThe intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs 31%) and extrahepatic disease (56% vs 32%, P = .02). The median numbers of chemotherapy cycles were similar (10 vs 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm at 2 (78% vs 54%, P = .02), 4 (95% vs 70%, P = .03), and 6 months (76% vs 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs 16%, P = .05), and there was improved median progression-free survival (15.3 vs 7.6 months).\n\n\nCONCLUSIONS\nThe simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This strategy leads to improved overall response rates, improved hepatic progression-free survival, and more durable overall progression-free survival in patients downsized to resection.", "affiliations": "Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, Kentucky.;Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, Kentucky.;Clearview Cancer Institute, Huntsville, Alabama.;Froedtert Medical College, Milwaukee, Wisconsin.;Interventional Radiology, Sutter Health, Sacramento, California.;Norton Radiology Associates, Louisville, Kentucky.;Norton Radiology Associates, Louisville, Kentucky.;Hospital Italiano, Buenos Aires, Argentina.;James Graham Brown Cancer Center, Louisville, Kentucky.;Providence Medical Center, Portland, Oregon.;Siteman Cancer Center, Washington University in Saint Louis/Barnes-Jewish Hospital, Saint Louis, Missouri.", "authors": "Martin|Robert C G|RC|;Scoggins|Charles R|CR|;Schreeder|Marshall|M|;Rilling|William S|WS|;Laing|Christopher J|CJ|;Tatum|Clifton M|CM|;Kelly|Lawrence R|LR|;Garcia-Monaco|Ricardo D|RD|;Sharma|Vivek R|VR|;Crocenzi|Todd S|TS|;Strasberg|Steven M|SM|", "chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin", "country": "United States", "delete": false, "doi": "10.1002/cncr.29534", "fulltext": null, "fulltext_license": null, "issn_linking": "0008-543X", "issue": "121(20)", "journal": "Cancer", "keywords": "hepatic artery therapy; irinotecan; liver-directed therapy; liver-dominant metastatic colorectal cancer; metastatic colon cancer", "medline_ta": "Cancer", "mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D015179:Colorectal Neoplasms; D016503:Drug Delivery Systems; D005472:Fluorouracil; D006499:Hepatic Artery; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D016896:Treatment Outcome", "nlm_unique_id": "0374236", "other_id": null, "pages": "3649-58", "pmc": null, "pmid": "26149602", "pubdate": "2015-10-15", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis.", "title_normalized": "randomized controlled trial of irinotecan drug eluting beads with simultaneous folfox and bevacizumab for patients with unresectable colorectal liver limited metastasis" }

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RANDOMIZED CONTROLLED TRIAL OF IRINOTECAN DRUG-ELUTING BEADS WITH SIMULTANEOUS FOLFOX AND BEVACIZUMAB FOR PATIENTS WITH UNRESECTABLE COLORECTAL LIVER-LIMITED METASTASIS. 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RANDOMIZED CONTROLLED TRIAL OF IRINOTECAN DRUG-ELUTING BEADS WITH SIMULTANEOUS FOLFOX AND BEVACIZUMAB FOR PATIENTS WITH UNRESECTABLE COLORECTAL LIVER-LIMITED METASTASIS. 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RANDOMIZED CONTROLLED TRIAL OF IRINOTECAN DRUG-ELUTING BEADS WITH SIMULTANEOUS FOLFOX AND BEVACIZUMAB FOR PATIENTS WITH UNRESECTABLE COLORECTAL LIVER-LIMITED METASTASIS. CANCER. 2015?3649-3658", "literaturereference_normalized": "randomized controlled trial of irinotecan drug eluting beads with simultaneous folfox and bevacizumab for patients with unresectable colorectal liver limited metastasis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151120", "receivedate": "20151120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11756911, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "BACKGROUND\nOmalizumab is a non-steroidal medication indicated for the treatment of poorly controlled moderate-to-severe allergic asthmatics. This observational study examines the \"real world\" effectiveness of omalizumab in this population.\n\n\nMETHODS\nThis is a one year open-label observational study that compared clinical outcomes including total oral corticosteroid use, exacerbation history, measures of quality of life and inflammation in patients with moderate-to-severe allergic asthma, who were prescribed omalizumab as part of their treatment with the year prior to therapy.\n\n\nRESULTS\nA total of 99 patients were enrolled at 25 sites in Canada. During the study period, the mean total annual OCS dose was reduced from 2301.5 mg (prednisone equivalents) in the year prior to omalizumab to 1130.0 mg (p<0.0001). There was a 71% reduction in asthma exacerbations and 56% of patients on omalizumab remained exacerbation free when compared to the year prior to study entry. Associated with this was reduced health care utilization. There were significant improvements in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) Patients with an elevated FeNO at baseline showed a better response to treatment. No new safety issues were identified during the study period.\n\n\nCONCLUSIONS\nOur study demonstrates that in \"real world\" clinical practice, after initiating omalizumab, there is a reduction in total OCS use and exacerbation frequency in patients with moderate-to-severe allergic asthma. Patients on treatment reported improved asthma control and quality of life. FeNO may be a useful biomarker to identify patients who may benefit with omalizumab treatment.", "affiliations": "Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.;Ottawa Allergy Research Corporation, University of Ottawa, Ottawa, Ontario, Canada.;Clinique Spécialisée en Allergie de la Capitale, Quebec City, Quebec, Canada.;Novartis Pharmaceuticals Canada Inc., Montreal, Quebec, Canada.;Novartis Pharmaceuticals Canada Inc., Montreal, Quebec, Canada.", "authors": "Bhutani|Mohit|M|http://orcid.org/0000-0002-7535-6613;Yang|William H|WH|;Hébert|Jacques|J|;de Takacsy|Frederica|F|;Stril|Jean-Louis|JL|", "chemical_list": "D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D005938:Glucocorticoids; D000069444:Omalizumab; D009569:Nitric Oxide; D011241:Prednisone", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0183869", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0183869PONE-D-17-12144Research ArticleMedicine and Health SciencesPulmonologyAsthmaMedicine and Health SciencesHealth CareQuality of LifeResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsResearch and Analysis MethodsResearch DesignObservational StudiesMedicine and Health SciencesPulmonologyRespiratory InfectionsResearch and Analysis MethodsResearch DesignSurvey ResearchQuestionnairesMedicine and Health SciencesHealth CareHealth Care PolicyTreatment GuidelinesMedicine and Health SciencesCritical Care and Emergency MedicineThe real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma: The ASTERIX Observational study The ASTERIX Observational studyhttp://orcid.org/0000-0002-7535-6613Bhutani Mohit ConceptualizationInvestigationMethodologyWriting – original draftWriting – review & editing1*Yang William H. ConceptualizationInvestigationMethodologyWriting – original draftWriting – review & editing2Hébert Jacques ConceptualizationInvestigationMethodologyWriting – original draftWriting – review & editing3de Takacsy Frederica ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationResourcesWriting – original draftWriting – review & editing4Stril Jean-Louis ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesValidationWriting – original draftWriting – review & editing41 \nDepartment of Medicine, University of Alberta, Edmonton, Alberta, Canada2 \nOttawa Allergy Research Corporation, University of Ottawa, Ottawa, Ontario, Canada3 \nClinique Spécialisée en Allergie de la Capitale, Quebec City, Quebec, Canada4 \nNovartis Pharmaceuticals Canada Inc., Montreal, Quebec, CanadaFehrenbach Heinz EditorForschungszentrum Borstel Leibniz-Zentrum fur Medizin und Biowissenschaften, GERMANYCompeting Interests: MB, WHY and JH received honoraria as part of the steering committee for the development of the research protocol. MB, WHY and JH are or have been members of Novartis Advisory Boards. J-LS and FdT are employees of Novartis Pharmaceuticals Canada Inc. J-LS is Therapeutic Area Head, Respiratory Division and FdT is the Group Head, Local Clinical Research Operations. This commercial affiliation of J-LS and FdT does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.\n\n* E-mail: [email protected] 8 2017 2017 12 8 e018386928 3 2017 11 8 2017 © 2017 Bhutani et al2017Bhutani et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nOmalizumab is a non-steroidal medication indicated for the treatment of poorly controlled moderate-to-severe allergic asthmatics. This observational study examines the “real world” effectiveness of omalizumab in this population.\n\nMethods\nThis is a one year open-label observational study that compared clinical outcomes including total oral corticosteroid use, exacerbation history, measures of quality of life and inflammation in patients with moderate-to-severe allergic asthma, who were prescribed omalizumab as part of their treatment with the year prior to therapy.\n\nResults\nA total of 99 patients were enrolled at 25 sites in Canada. During the study period, the mean total annual OCS dose was reduced from 2301.5 mg (prednisone equivalents) in the year prior to omalizumab to 1130.0 mg (p<0.0001). There was a 71% reduction in asthma exacerbations and 56% of patients on omalizumab remained exacerbation free when compared to the year prior to study entry. Associated with this was reduced health care utilization. There were significant improvements in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) Patients with an elevated FeNO at baseline showed a better response to treatment. No new safety issues were identified during the study period.\n\nConclusion\nOur study demonstrates that in “real world” clinical practice, after initiating omalizumab, there is a reduction in total OCS use and exacerbation frequency in patients with moderate-to-severe allergic asthma. Patients on treatment reported improved asthma control and quality of life. FeNO may be a useful biomarker to identify patients who may benefit with omalizumab treatment.\n\nhttp://dx.doi.org/10.13039/100009009Novartis Pharmaceuticals CanadaMB, WHY and JH received honoraria as part of the steering committee for the development of the research protocol. MB, WHY and JH are members of Novartis Advisory Boards. Novartis Pharmaceuticals Canada Inc. provided funding for the development and implementation of this observational study. This included support for the individual sites to collect data for the duration of the study. They also funded the analysis of the study. No study medication was funded by Novartis as this was an observational trial only. Study medication was supplied through public and private payers, as the patients enrolled in the study met the Canadian product monograph for the utilization of omalizumab in the severe asthma population. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nAsthma is a chronic inflammatory airway disease characterized by variable airflow obstruction. Asthmatics are able to achieve control of their symptoms by limiting environmental exposures that may aggravate their asthma and by using medications such as inhaled corticosteroids (ICS) to reduce the inflammation associated with the disease.\n\nHowever, there remains a population of asthmatics who, despite guideline-based treatment, continue to have poor control and experience acute exacerbations [1]. These patients often require oral corticosteroids (OCS) to control their disease. OCS are associated with a number of side effects including osteoporosis, cataracts and the potential for Cushing’s syndrome [2]. Since asthma is more severe in older adults [3], reducing the burden of OCS is of high importance.\n\nApproximately 90% of asthma is allergic in nature [4]. Omalizumab is a biologic humanized IgE neutralizing antibody (anti-IgE) that binds to circulating IgE, prevents binding to the receptor thereby inhibiting the allergic-inflammatory cascade [5]. Omalizumab provides a non-steroidal treatment option for asthmatics with moderate to severe persistent allergic asthma, whose symptoms are inadequately controlled with high dose ICS [6]. Previously, omalizumab has been shown to reduce the number of asthma exacerbations, improve symptom severity, and improve the quality of life in such patients [7–9]. It is currently recommended in many asthma guidelines, including the Canadian guidelines [1], as part of a treatment algorithm [10].\n\nThe purpose of this study is to understand the ‘real world’ efficacy and safety of omalizumab in the treatment of patients with moderate-to-severe allergic asthma (the ASTERIX Observational study). The primary aim of this study was to evaluate the corticosteroid-sparing effect of omalizumab in these patients.\n\nMethods\nStudy design\nThis was a pan Canadian, multicenter, 12-month, open-label single-arm study. At each institution, the research protocol was reviewed by the institutions ethics board (see below) and the study received institutional approval. This study is an observational study of patient related outcomes. The study medication is already approved for use in Canada, and the patients enrolled in the study were deemed to be appropriate for the use of omalizumab, as per the indications on the Canadian product monograph. Our study is assessing a real life response to the therapy. The study began in August 2012 (first patient, first visit) and completed in October 2014 (last patient, last visit). The study collected retrospective and prospective information from subjects who were to be prescribed omalizumab in routine clinical practice as per the Canadian Product Monograph [6]. Eligible study participants had inadequately-controlled asthma, defined as either: 1) having experienced two or more severe asthma exacerbations requiring treatment with OCS in the 12 months preceding study enrolment despite treatment with high dose ICS plus at least one other controller agent; or 2) requiring a maintenance dose of OCS for at least 3 months prior to study enrolment, independent of exacerbation history. During the study, subjects received treatment for their asthma and any acute asthma exacerbations as clinically indicated and as per usual medical practice.\n\nStudy eligibility criteria excluded subjects previously treated with omalizumab, subjects with a respiratory tract infection in the month prior to study start, current smokers or subjects with a smoking history of >10 pack-years, subjects with severe co-morbidities, or subjects who were pregnant or lactating.\n\nBaseline assessments were completed prior to the first omalizumab injection and subjects were then assessed every three months during the study. At each assessment, pulmonary function was measured, medication use and exacerbation data were collected. The term “severe asthma exacerbation” was defined for this study as one that required treatment with systemic (oral or IV) corticosteroids and/or that resulted in a hospitalization or emergency department visit. Subjects also completed the Asthma Control Questionnaire (ACQ) and the Asthma Quality of Life Questionnaire (AQLQ). The ACQ is a seven-item questionnaire that is a validated assessment of asthma symptom control [11,12]. The AQLQ is a disease-specific, self-administered quality of life questionnaire [13] which can be used to evaluate the impact of asthma treatment over the prior 14 days.\n\nFractional exhaled nitric oxide (FeNO) was measured in a subset of enrolled subjects at 10 sites. Each of the 10 sites participating in this exploratory analysis had access to appropriate equipment for measuring FeNO, using standardized techniques and calibration procedures. Two FeNO tests were conducted on each subject at every study visit, and the reported value was the mean of 2 values that were within 10% of each other.\n\nRetrospective data for a period of 12 months prior to the first omalizumab injection was collected from subject charts for comparison with data collected from the 12-month prospective study period. This data included: cumulative systemic corticosteroid dosage, frequency and severity of asthma exacerbations, symptom scores, quality-of-life data and health care utilization [14].\n\nEfficacy outcomes\nThe primary endpoint was the mean change in total annual OCS dose during the prospective treatment period as compared to the year prior to the start of omalizumab treatment. Secondary endpoints included the number (%) of subjects who reduced/stopped OCS use, the number (%) of subjects experiencing severe asthma exacerbations, the mean number of severe asthma exacerbations per subject, mean duration of severe asthma exacerbations, changes in ACQ, AQLQ and FeNO while receiving omalizumab as compared to baseline or the prior year. Health resource utilization data was also collected prospectively and compared to the prior year.\n\nSafety outcomes\nOnly serious adverse events were collected for study purposes.\n\nStatistical analysis/outcome measures\nStatistical analyses were performed using the intent-to-treat (ITT) population. Descriptive statistics for continuous variables are presented with number of subjects, mean, standard deviation, median, minimum, and maximum. Comparisons between the prospective treatment period and retrospective data were performed using paired t-tests. Categorical variables were summarized with number and percentage of subjects. All hypotheses were based on two-sided tests using a 5% level of significance. The 95% confidence interval was calculated for the absolute difference between the treatment groups. Any other statistical tests were assessed at the 2-sided, 5% significance level.\n\nThe study protocol was approved by the institutional ethics board for each site, and all subjects (or parents/guardians when appropriate) provided written informed consent prior to any study-related evaluations. The following are the names of the ethics board/committee for each site involved in the study: Institutional Review Board Services (IRB Services), Aurora, Ontario; The Health Research Ethics Board (HREB)—Biomedical Panel, University of Alberta; Research Ethics Review Committee (RERC), Edmonton, Alberta; McGill University Health Center–Research Ethic Board (MUHC-REB), University of McGill; Comité d’Éthique à la Recherche–Centre Hospitalier de l’Université de Montréal (CER-CHUM), Centre Hospitalier de l’Université de Montréal; Comité d’Éthique à la Recherche–Institut Universitaire de Cardiologie et Pneumologie de Québec (CER IUCPQ), Institut Universitaire de Cardiologie et Pneumologie de Québec; University of British Columbia–Clinical Research Ethic Board (UBC CREB), University of British Columbia; University of British Columbia–Providence Health Care–Research Ethics Board (UBC-PHC REB, University of British Columbia.\n\nResults\nA total of 99 subjects were enrolled at 25 sites in Canada. All subjects received at least one dose of omalizumab during the study period. Twenty-one subjects (21.2%) discontinued the study. The primary reasons for discontinuation were loss to follow-up (9 subjects), administrative reasons (5 subjects), adverse events (4 subjects) and subject no longer required study drug (3 subjects). Of the 4 subjects who discontinued due to adverse events, there were 3 serious and one non-serious event: 1 case of pregnancy, 1 case of anaphylactic reaction, 1 case of severe asthma and one subject who discontinued due to an unspecified non-serious adverse event.\n\nTable 1 summarizes baseline characteristics. The subjects were predominantly female, white and with a mean age of 48. On average, they experienced 2.4 exacerbations in the year prior to starting treatment. Baseline medications are in keeping with current standards of asthma management.\n\n10.1371/journal.pone.0183869.t001Table 1 Demographics and baseline characteristics.\nBaseline characteristics n = 99\t\nAge (years)\tMean (SD)\t47.8 (13.8)\t\nRange\t12–77\t\nGender, n (%)\tMale\t31 (31.3%)\t\n\tFemale\t68 (68.7%)\t\nRace, n (%)\tWhite\t87 (87.9%)\t\nBlack\t5 (5.1%)\t\nAsian\t5 (5.1%)\t\nNative American\t2 (2.0%)\t\nWeight (kg)\tMean (SD)\t79.6 (19.7)\t\nRange\t37–139\t\nDuration of asthma (years)\tMean (SD)\t20.9 (15.4)\t\nSmoking history, n (%)\tNever smoked\t63 (63.6%)\t\nEx-smoker\t36 (36.4%)\t\nFEV1 (L)\tMean (SD)\t2.2 (0.8)\t\nFEV1 (% predicted)\tMean (SD)\t72.9 (20.1)\t\nIgE levels (ng/mL)\tMean (SD)\t668.1 (937.0)\t\n\nExacerbations in 12 months before baseline visit\tMean (SE)\t2.4 (0.14)\t\nMean (SE)\t2.4 (0.14)\t\nRange\t0.0–8.0\t\nAsthma Medications taken at Visit 1*\tInhaled Corticosteroids\t46 (46.5%)\t\nLong-Acting Bronchodilators\t3 (3.0%)\t\nLABA/ICS (combination)\t93 (93.9%)\t\nLeukotriene Receptor Antagonists\t52 (52.5%)\t\nLABA = Long Acting Bronchodilator; ICS = Inhaled Corticosteroid.\n\n*A subject could have had more than one type of asthma medication.\n\nAll but one subject had documented prior systemic corticosteroid use. The majority used OCS periodically for the treatment of asthma exacerbations and 25% used a daily OCS maintenance dose for asthma management. When treated with omalizumab, the mean total annual OCS dose (expressed in prednisone equivalents) was reduced from 2301.5 mg (SE 374.3 mg) to 1130.0 mg (SE 307.5 mg) (p<0.0001) (Table 2). 70.8% of subjects either stopped or were able to reduce the dose of OCS by 40% or more.\n\n10.1371/journal.pone.0183869.t002Table 2 Mean change in total annual oral corticosteroid (OCS) dose [1] (ITT population).\n\tRetrospective Period\tProspective Period\t\nN\t96\t96\t\nMean (SE)\t2301.5 (374.3)\t1130.0 (307.5)\t\nRange\t(0.0, 30780)\t(0.0, 21840)\t\nRetrospective—Prospective [2]\t\t\n • Difference (SE)\t1171.5 (197.8)\t\n • 95% CI\t[778.8, 1564.2]\t\n • p-value\t<0.0001\t\n[1] Oral Corticosteroid values are converted to prednisone equivalents (expressed in mg).\n\n[2] Paired t-test was used to assess period differences.\n\nSE = standard error\n\nOf the 96 subjects in the ITT population with available data, 54 patients (56.3%) remained exacerbation-free during the prospective period, as compared to only 4 patients (4.2%) in the retrospective period (Table 3). The overall exacerbation frequency was reduced by 70.8% during the study period, with a mean of 0.8 severe exacerbations/patient compared to 2.4/patient in the year prior (p<0.0001). Additionally, the mean duration of severe asthma exacerbations was decreased from 39.1 to 10.9 days, (p<0.0001).\n\n10.1371/journal.pone.0183869.t003Table 3 Number (%) of subjects experiencing severe asthma exacerbations [1] and change from baseline health resource utilization (ITT population).\n\t\tRetrospective period\tProspective period\t\nSevere asthma\n Exacerbation\n\tN\t96\t96\t\nNo\t4 (4.2%)\t54 (56.3%)\t\nYes\t92 (95.8%)\t42 (43.8%)\t\nNumber of emergency department (ED) visits\tN\t95\t96\t\nMean (SE)\t1.2 (0.1)\t0.2 (0.1)\t\nMedian\t1.0\t0.0\t\nRange\t(0.0, 7.0)\t(0.0, 5.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t1.1 (0.2)\t\n• 95% CI\t[-0.8,1.4]\t\n• p-value\t<0.0001\t\nNumber of hospitalizations\tN\t96\t96\t\nMean (SE)\t0.4 (0.1)\t0.1 (0.1)\t\nMedian\t0.0\t0.0\t\nRange\t(0.0, 5.0)\t(0.0, 4.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t0.3 (0.1)\t\n• 95% CI\t[-0.1, 0.5]\t\n• p-value\t0.0081\t\nNumber of unscheduled health professional visits\tN\t87\t95\t\nMean (SE)\t3.1 (0.4)\t0.8 (0.2)\t\nMedian\t3.0\t0.0\t\nRange\t(0.0, 20.0)\t(0.0, 8.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t2.4 (0.4)\t\n• 95% CI\t[1.7, 3.1]\t\n• p-value\t<0.0001\t\nNumber of days in hospital (ED+ICU+Other)\tN\t96\t96\t\nMean (SE)\t1.8 (0.3)\t0.6 (0.3)\t\nMedian\t0.0\t0.0\t\nRange\t(0.0, 18.0)\t(0.0, 22.0)\t\nRetrospective—Prospective [2]\t\t\n• Difference (SE)\t1.3 (0.4)\t\n• 95% CI\t[0.5, 2.0]\t\n• p-value\t0.0010\t\n[1] A severe asthma exacerbation had to fulfil at least one of the following criteria: 1) requiring treatment with systemic (oral or IV) corticosteroids OR 2) resulting in hospitalization or requiring an emergency department visit. Courses of corticosteroids separated by 1 week or more were treated as separate severe exacerbation events\n\n[2] Paired t-test was used to assess period differences.\n\nOmalizumab treatment resulted in improved asthma control, as shown through significant improvements in the mean ACQ total score, from 2.7 at baseline to 1.9 at month 4 (p<0.0001). This improvement was maintained until the end of the study (Table 4). In parallel, the AQLQ score improved from an average of 3.9 at baseline to 4.8 at month 4 (p<0.0001) (Table 5) and remained stable for the remainder of the study. The domain scores all improved by a similar magnitude.\n\n10.1371/journal.pone.0183869.t004Table 4 Change from baseline in Asthma Control Questionnaire (ACQ) total score [1] during the prospective period (ITT population).\n\tBaseline\tMonth 4\tMonth 8\tMonth 12\t\nN\t96\t92\t76\t86\t\nMean (SE)\t2.7 (0.1)\t1.9 (0.1)\t1.8 (0.1)\t1.9 (0.1)\t\nMedian\t2.6\t1.8\t1.7\t1.8\t\nRange\t(0.0, 5.6)\t(0.0, 4.6)\t(0.0, 4.0)\t(0.0, 4.7)\t\nBaseline—Treatment\t\t\t\t\t\n • Difference (SE)\t\t0.7 (0.1)\t1.0 (0.1)\t0.8 (0.1)\t\n • 95%CI\t\t[0.5, 1.0]\t[0.8, 1.2]\t[0.5, 1.1]\t\n • p-value\t\t<0.0001\t<0.0001\t<0.0001\t\n[1] Each question is equally weighted and the ACQ score is the mean of the 7 questions with an average value between 0 (totally controlled) and 6 (severely uncontrolled). Paired t-test was used to assess differences between baseline and treatment values.\n\n10.1371/journal.pone.0183869.t005Table 5 Change from baseline in Asthma Quality of Life Questionnaire (AQLQ) total scores during treatment with omalizumab (ITT population).\n\tBaseline\tMonth 4\tMonth 8\tMonth 12\t\nAverage Overall Score\t\nN\t96\t92\t76\t86\t\nMean (SE)\t3.9 (0.1)\t4.8 (0.1)\t5.0 (0.1)\t4.8 (0.2)\t\nMedian\t3.9\t4.9\t5.1\t4.9\t\nRange\t(1.4, 6.7)\t(1.8, 6.8)\t(1.8, 6.9)\t(1.6, 6.9)\t\nBaseline—treatment [1]\t\t\t\t\t\n • Difference (SE)\t\t-0.9 (0.1)\t-1.2 (0.1)\t-1.0 (0.2)\t\n • 95% CI\t\t[-1.2, -0.6]\t[-1.5, -0.9]\t[-1.3, -0.7]\t\n • p-value\t\t<0.0001\t<0.0001\t<0.0001\t\n[1] Paired t-test was used to assess differences between baseline and treatment values.\n\nFeNO was measured on 48 subjects during the study period. Table 6 summarizes the change in FeNO measurements over the course of the study period. Mean FeNO at baseline was 47.3 ppb (SE 5.7) and was significantly reduced by 12 months to 37.1 ppb (SE 4.6, p = 0.0258). Subjects were further divided into high (≥19.5 ppb) and low (<19.5) baseline FeNO groups for analysis purposes (Table 7) [15]. There was a higher percent reduction in total annual OCS dose and annual number of severe asthma exacerbations in the high FeNO subgroup than in the Low FeNO group. In the high FeNO group, the annual OCS dose decreased by 75% and exacerbations were reduced by 82%.\n\n10.1371/journal.pone.0183869.t006Table 6 Change from baseline in Forced Exhaled Nitric Oxide (FeNO) mean values [1] during the prospective period (ITT / FeNO population).\n\tBaseline\tMonth 4\tMonth 8\tMonth 12\t\nN\t48\t46\t47\t49\t\nMean (SE)\t47.3 (5.7)\t39.1 (5.0)\t38.0 (6.0)\t37.1 (4.6)\t\nMedian\t39.3\t26.5\t23.5\t22.0\t\nRange\t(6.5, 173.5)\t(5.5, 161.5)\t(5.0, 238.5)\t(5.0, 140.0)\t\nBaseline—treatment [2][3]\t\t\t\t\t\n • Difference(SE)\t\t7.6 (4.0)\t9.0 (4.8)\t9.9 (4.3)\t\n • 95% CI\t\t[-0.5, 15.7]\t[-0.6, 18.6]\t[1.2, 18.5]\t\n • p-value\t\t0.0660\t0.0642\t0.0258\t\n[1] The FeNO values (in ppb) used for the summary were the mean of 2 values obtained at each visit.\n\n[2] Paired t-test was used to assess differences between baseline and treatment values.\n\n[3] This analysis was conducted on a subset of subjects at 10 pre-defined sites.\n\nNote: Last observation forward methods (LOCF) were used for missing data.\n\n10.1371/journal.pone.0183869.t007Table 7 Percent change in total annual OCS dose and number of severe asthma exacerbations in Low/High FeNO baseline subgroups from baseline to end of prospective period (ITT population).\n\t\t% change in total annual OCS dose [1]\t% change in total annual number of severe asthma exacerbations [2]\t\nHigh FeNO [3]\tN\t35\t35\t\nMean (SE)\t-75.21 (5.5)\t-81.8 (4.9)\t\nMedian\t-100.0\t-100.0\t\nRange\t(-100.0, 0.3)\t(-100.0, 0.0)\t\nLow FeNO [3]\tN\t13\t13\t\nMean (SE)\t-27.6 (25.0)\t-47.4 (18.4)\t\nMedian\t-52.6\t-66.7\t\nRange\t(-100.0, 182.2)\t(-100.0, 100.0)\t\n[1] Oral corticosteroid values were converted to prednisone equivalents (mg).\n\n[2] Percent change was defined as 100*(Prospective—Retrospective)/Retrospective.\n\n[3] Low FeNO = FeNO measurement <19.5 ppb at baseline; High FeNO = FeNO measurement ≥19.5 ppb.\n\nNote: Two subjects had no severe asthma exacerbation during the Retrospective period but had one during the Prospective period. Therefore, % change could not be computed for these subjects.\n\nTable 3 summarizes the change in healthcare resource utilization during the study period. The mean number of Emergency Department visits (0.2 ± 0.1 vs 1.2 ± 0.1, p<0.0001), hospitalizations (0.1 ± 0.1 vs 0.4 ± 0.1, p = 0.0081) and unscheduled healthcare professional visits (0.8 ± 0.2 vs 3.1 ± 0.4, p<0.0001) were all significantly reduced during the treatment follow up period. In addition, hospitalized subjects had a significantly reduced length of stay (0.6 ± 0.3 vs 1.8 ± 0.3 days; p<0.0010).\n\nSafety\nIn the study database, nine subjects experienced at least one SAE (Serious Adverse Event) but only one subject experienced an SAE considered by the investigator to be related to study drug. That subject had three events—dizziness of moderate intensity on the first day of treatment and 2 anaphylactic reactions of severe intensity. Omalizumab was permanently discontinued for this subject. The subject was reported to have completely recovered from these events. Table 8 summarizes all SAEs reported during the study. No safety concerns were raised from these SAEs. One subject became pregnant and was discontinued from the study.\n\n10.1371/journal.pone.0183869.t008Table 8 All Serious adverse events.\nSystem Organ Class\tOmalizumab (N = 99)\t\n Preferred Term\tn (%)\t\nInfections and Infestations\t\t\n Abscess\t1 (1%)\t\n Device related infection\t1 (1%)\t\n Post procedural infection\t1 (1%)\t\n Staphylococcal infection\t1 (1%)\t\nInjury, poisoning and procedural complications\t\n Anaemia postoperative\t1 (1%)\t\n Procedural haemorrhage\t1 (1%)\t\n Wrist fracture\t1 (1%)\t\nCardiac disorders\t\t\n Cardiac arrest\t1 (1%)\t\nGastrointestinal disorders\t\t\n Large intestinal obstruction\t1 (1%)\t\nImmune system disorders\t\t\n Anaphylactic reaction\t1 (1%)\t\nNervous system disorders\t\t\n Dizziness\t1 (1%)\t\nPregnancy, puerperium and perinatal conditions\t\n Pregnancy\t1 (1%)\t\nRenal and urinary disorders\t\t\n Renal impairment\t1 (1%)\t\nRespiratory, thoracic and mediastinal disorders\t\n Asthma\t1 (1%)\t\nDiscussion\nAmong the asthmatic population, the prevalence of severe uncontrolled asthma is approximately 10% [16,17]. These patients have a reduced quality of life and poor lung function. For many of them, systemic corticosteroids are routinely used to manage the disease, and as a result, they are prone to a variety of short and long-term adverse effects [2], which may further add to the clinical burden of this disease. In randomized clinical trials omalizumab, through its non-steroidal mechanism of action of binding free IgE molecules and preventing activation of the inflammatory cascade, has been shown to reduce asthma exacerbations and thereby reduce the need for oral corticosteroids [8,9]. However, until now the Canadian real-life effect has not been assessed. The present study was designed to evaluate the “real life” clinical benefit of omalizumab as add-on treatment for patients with poorly controlled moderate-to-severe allergic asthma, as per Canadian guidelines [1].\n\nOur results demonstrate that patients treated with omalizumab reduced their total oral corticosteroid dosing during the treatment period, when compared with the year prior. Furthermore, 50% of the patients were able to discontinue use of daily OCS during the study. There are significant benefits to this, as long-term OCS use is associated with many side effects negatively affecting a patient’s overall health. These include increased risk of infections, hypertension, cataracts, impact on bone mineral density and the potential to lead to diabetes or affect diabetic control [2].\n\nPrevention of asthma exacerbations is an important outcome of asthma treatment [1, 10]. Our study demonstrated a significant reduction in the frequency, severity and duration of asthma exacerbations. Although mortality due to asthma has decreased significantly, the morbidity and costs associated with asthma exacerbations remain elevated [16,18,19]. In our study, we saw a 71% reduction in total asthma exacerbations along with reduced health care utilization. In several studies, the improved outcomes we observed has resulted in a cost benefit favoring use of omalizumab, especially in those with severe exacerbations requiring hospitalizations [20,21].\n\nFeNO is considered to be a non-invasive marker for airway inflammation [22] and has been utilized as a surrogate marker for the presence of eosinophilic airway dysfunction. In this study, we observed a significant reduction in FeNO levels over the 1-year study period. The FeNO decrease occurred despite reduced OCS exposure, supporting the anti-inflammatory effect of omalizumab. Furthermore, the clinical benefits of omalizumab were more pronounced in patients who had high FeNO levels at baseline. There was a 75% reduction in annual OCS use and an 82% reduction in exacerbation rates in patients with a FeNO ≥19.5 ppb. This supports the findings of Hanania et al.[15] who demonstrated a similar finding in the EXTRA study. FeNO, if used as part of the clinical assessment, may further assist in identifying an omalizumab responder, which is of benefit for patient and physician.\n\nAccording to the Canadian asthma management continuum [1], improved quality of life (QoL) and symptom control are important goals of treatment. The subjects enrolled in this study had poor QoL and suboptimal control of their asthma at baseline, as measured by the ACQ and AQLQ. The AQLQ is a disease-specific questionnaire which measures the impact of asthma on symptoms, activity limitation, emotional function and environmental stimuli [13]. In this study, omalizumab treatment led to a significant improvement in AQLQ scores. The improvements were seen early, by month 4, and were maintained throughout the assessment period. In parallel, the ACQ demonstrated a similar early significant improvement in asthma symptoms and these were also maintained over the course of the study. It is important to highlight that all the improved outcomes observed during the study occurred in the setting of reduced OCS exposure, which has its own clinical merit and further supports the efficacy of omalizumab.\n\nAlthough only 5–10% of asthmatics have severe disease, they account for more than 50% of asthma-related total health costs [18,23]. Our results show that adding omalizumab to the therapeutic regimen of these severe asthmatics significantly reduced overall health care utilization. Reductions in healthcare utilization with omalizumab have been previously reported [7,9,24–26], and it is encouraging, that in “real life” application, this continues to be seen.\n\nASTERIX is an observational, open-label study and the results are consistent with published randomized clinical trials and other “real life effectiveness” studies [7–9,27], however this is the first report in a Canadian population and the first to report on the use of FeNO in “real life” Canadian clinical practice. Recently both a systematic review and meta-analysis assessing “real life effectiveness” studies of omalizumab have been published [28, 29]. The outcomes assessed and reported in those studies were similar to ours, and show that in different populations, there is a “real life effectiveness” of omalizumab in improving the outcomes for patients with severe asthma.\n\nThe results of our study in a Canadian population adds to the current literature in several capacities. First, there are inherent differences in the Canadian population than the ones studied in the systematic review and meta-analysis, as those studies were primarily European. Second, because health care systems vary between countries, the medical treatment a patient receives prior to the initiation of omalizumab may vary, and thereby affect the outcomes of previous reports. Third, demonstrating efficacy in the Canadian severe asthma population will be helpful to payers of the health care system in Canada, both private and public, who may request evidence of efficacy in order to fund this medication. Lastly, unique to our study was the measurement of FeNO in a sub-set of the study population. The impressive response to omalizumab in patient’s with high FeNO (>19.5 ppb) has not been reported in other “real life” studies. Based on both the EXTRA and Asterix study, clinicians may want to consider measuring FeNO to provide more confidence in the decision to add on omalizumab to current therapy in the uncontrolled severe asthma patient.\n\nThere are several limitations to this study. First, it is an open-label study and there is no control group for comparison. Instead, treatment effectiveness was assessed in comparison to the previous year or to patient status at baseline (AQLQ, ACQ). Second, it could be considered a weakness that some of the study data (exacerbations, OCS use and acute care visits) was collected retrospectively. However, subjects with this severity of asthma tend to be followed closely by their physicians so that there is a good record of treatment in the patient chart. If anything, some retrospective events might not have been reported and the results may therefore underestimate the treatment effect.\n\nConclusion\nIn a “real world” observational study, patients with moderate-to-severe allergic asthma who are poorly controlled despite optimized therapy with high dose ICS and another controller medication, benefit from treatment with omalizumab by reducing oral steroid use, experiencing reduced exacerbation frequency and showing improved quality of life and asthma control.\n\nGuarantor: J-LS takes responsibility (is the guarantor) of the content of the manuscript, including data and analysis.\n\nAuthor contributions: MB, WHY, JH, FdT and J-LS contributed substantially to the study design, analysis and interpretation, and the writing of the manuscript. We also acknowledge Suzanne Kelly PhD in assisting in reviewing this manuscript.\n\nRole of the sponsor: Novartis Pharmaceuticals, Canada Inc. was the sponsor of this study. Support for protocol development, study implementation, data management and statistical analysis was provided by Allphase Clinical Research Inc. and funded by Novartis Pharmaceuticals, Canada Inc.\n\nOther Contributions: We thank the physicians who participated in the ASTERIX study: Dr. Mohit Bhutani, Dr.Jacques Hebert, Dr.William H. Yang, Dr. Celine Bergeron, Dr. Stephen Betschel, Dr. Joseph Braidy, Dr. Amarjit Cheema, Dr. David Copeland, Dr. François Corbeil, Dr. Delbert Dorscheid, Dr. Tam Le Duc, Dr. J. Mark FitzGerald, Dr. Charles Frankish, Dr. Michel Laviolette, Dr. Jason K. Lee, Dr. Marcel Mallet, Dr. Lyle Melenka, Dr. Marie-Chantal Menard, Dr. Ronald Olivenstein, Dr. Bruno Paradis, Dr. Bonavuth Pek, Dr. Warren Ramesh, Dr. Gordon Sussman, Dr. Ellie Tsai andDr. Shahin Zanganeh.\n==== Refs\nReferences\n1 Lougheed MD , Lemiere C , Dell SD , Ducharme FM , Fitzgerald JM , Leigh R , et al (2010 ) Canadian Thoracic Society Asthma Management Continuum—2010 Consensus Summary for children six years of age and over, and adults . Can Respir J \n17 : 15 –24 . 20186367 \n2 Schellenberg RR , Adachi JDR , Bowie D , Brown J , Guenther L , Kader T , et al (2007 ) Oral corticosteroids in asthma: A review of benefits and risks . Can Resp J \n14 : 1C –7C .\n3 Zein JG , Dweik RA , Comhair SA , Bleecker ER , Moore WC , Peters SP , et al (2015 ) Asthma Is More Severe in Older Adults . PLoS One \n10 : e0133490 \ndoi: 10.1371/journal.pone.0133490 \n26200463 \n4 Holt PG , Macaubas C , Stumbles PA , Sly PD (1999 ) The role of allergy in the development of asthma . 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Allergy \n2016 ; 71 : 593 –610 \ndoi: 10.1111/all.12815 \n26644231 \n29 Alhossan A , Lee C , MacDonald K , Abraham I (2017 ) “Real-life” Effectiveness Studies of Omalizumab in Adult Patients with Severe Allergic Asthma: Meta-analysis . J Allergy Clin Immunol Pract 2017: online\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "12(8)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents; D001249:Asthma; D015415:Biomarkers; D018450:Disease Progression; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D045853:Exhalation; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide; D000069444:Omalizumab; D010342:Patient Acceptance of Health Care; D011241:Prednisone; D011788:Quality of Life; D012720:Severity of Illness Index; D016896:Treatment Outcome", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0183869", "pmc": null, "pmid": "28859150", "pubdate": "2017", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": "20956126;20940232;20483574;25439368;17711616;19619998;18425299;11029340;23471469;11843329;26644231;26200463;11922396;20186367;28351783;15679715;16099149;18445184;10586890;10573240;9877485;8466117;17076981;15817806;22954018;21255035", "title": "The real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma: The ASTERIX Observational study.", "title_normalized": "the real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma the asterix observational study" }

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{ "abstract": "The major cardiovascular (CV) adverse effects observed with sipuleucel-T from large multi-institutional clinical trials included thromboembolic events, myocardial infarction, and congestive heart failure in up to 0.3% of patients with CV risk factors. The incidence, outcomes, and mechanisms in real-world clinical settings of these CV adverse effects to date have not been fully elucidated. Our study identified a patient with sipuleucel-T-induced inflammatory cardiomyopathy, which led to the identification of CV adverse effects associated with sipuleucel-T from a large pharmacovigilance database and elucidation of its potential mechanisms.\n\n\n\nUsing the MedDRA term 'cardiac disorders' (System Organ Class level), CV adverse events associated with sipuleucel-T versus all other drugs were reviewed from VigiBase, a large pharmacovigilance database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator. A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. From VigiBase, the total number of CV adverse drug reaction reported with sipuleucel-T was 306 out of a total of 22 980 104 adverse drug reactions in VigiBase on 10/25/2020. MedDRA preferred terms levels were grouped into major CV adverse drug reaction categories where we observed significant reports of myocardial ischaemia, supraventricular tachycardia (particularly atrial fibrillation/atrial flutter), congestive heart failure, and valvular disorders. Myocardial ischemia included acute myocardial infarction (IC025 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with 'cardiac failure congestive' (IC025 1.5), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases considered to be solely due to sipuleucel-T.\n\n\n\nPatients with CV risk factors who are receiving sipuleucel-T may be at higher risk for congestive heart failure, myocardial ischemia, and supraventricular tachycardia. Electrocardiograms during weekly sipuleucel-T infusions and left ventricular function monitoring with echocardiogram should be considered in these patients. Our findings are suggestive of another rare presentation of T-cell-mediated CV toxicity with cancer immunotherapy.", "affiliations": "Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Internal Medicine, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Pathology and Laboratory Medicine, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Pathology and Laboratory Medicine, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Marion L. Shepard Cancer Center, Washington, NC, USA.;Department of Hematology and Oncology, Vidant Medical Center/East Carolina University, Greenville, NC, USA.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Pharmacology, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Sorbonne Université, INSERM CIC-1901, AP-HP, Paris, France.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA.;Department of Pharmacology, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Sorbonne Université, INSERM CIC-1901, AP-HP, Paris, France.", "authors": "Moey|Melissa Y Y|MYY|0000-0002-8117-0487;Jiwani|Rahim A|RA|0000-0002-1324-865X;Takeda|Kotaro|K|;Prenshaw|Karyn|K|;Kreeger|R Wayne|RW|;Inzerillo|John|J|;Liles|Darla K|DK|0000-0003-1480-7887;Marcu|C Bogdan|CB|0000-0001-5444-9573;Lebrun-Vignes|Bénédicte|B|0000-0001-6676-5063;Morris|D Lynn|DL|;Ardhanari|Sivakumar|S|;Salem|Joe-Elie|JE|0000-0002-0331-3307", "chemical_list": "D014020:Tissue Extracts; C511774:sipuleucel-T", "country": "England", "delete": false, "doi": "10.1002/ehf2.13400", "fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822\nJohn Wiley and Sons Inc. Hoboken\n\n33938158\n10.1002/ehf2.13400\nEHF213400\nESCHF-20-00821\nShort Communication\nShort Communications\nSipuleucel‐T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database\nSipuleucel‐T associated inflammatory cardiomyopathy\nM.Y.Y. Moey et al.\nMoey Melissa Y.Y. https://orcid.org/0000-0002-8117-0487\n1 [email protected]\n\nJiwani Rahim A. https://orcid.org/0000-0002-1324-865X\n2\nTakeda Kotaro 3\nPrenshaw Karyn 3\nKreeger R. Wayne 1\nInzerillo John 4\nLiles Darla K. https://orcid.org/0000-0003-1480-7887\n5\nMarcu C. Bogdan https://orcid.org/0000-0001-5444-9573\n1\nLebrun‐Vignes Bénédicte https://orcid.org/0000-0001-6676-5063\n6 7\nMorris D. Lynn 1\nArdhanari Sivakumar 1\nSalem Joe‐Elie https://orcid.org/0000-0002-0331-3307\n6 8 9\n1 Department of Cardiovascular Sciences, East Carolina Heart Institute Vidant Medical Center/East Carolina University 115 Heart Drive Greenville NC 27834 USA\n2 Department of Internal Medicine Vidant Medical Center/East Carolina University Greenville NC USA\n3 Department of Pathology and Laboratory Medicine Vidant Medical Center/East Carolina University Greenville NC USA\n4 Marion L. Shepard Cancer Center Washington NC USA\n5 Department of Hematology and Oncology Vidant Medical Center/East Carolina University Greenville NC USA\n6 Department of Pharmacology, Regional Pharmacovigilance Centre Pitié‐Salpêtrière Hospital, Sorbonne Université, INSERM CIC‐1901, AP‐HP Paris France\n7 EA Epiderme‐Epidemiology in Dermatology and Evaluation of Therapeutics Université Paris‐Est Créteil Créteil France\n8 UNICO‐GRECO APHP.Sorbonne Cardio‐Oncology Program Sorbonne Université Paris France\n9 Division of Cardiovascular Medicine, Cardio‐Oncology Program Vanderbilt University Medical Center Nashville TN USA\n* Correspondence to: Melissa Y. Y. Moey, MD MSc, Department of Cardiovascular Sciences, East Carolina Heart Institute, Vidant Medical Center/East Carolina University, 115 Heart Drive, Greenville, NC 27834, USA. Tel: +1 252‐744‐4400. Email: [email protected]\n02 5 2021\n8 2021\n8 4 10.1002/ehf2.v8.4 33603368\n25 2 2021\n18 8 2020\n22 4 2021\n© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nAims\n\nThe major cardiovascular (CV) adverse effects observed with sipuleucel‐T from large multi‐institutional clinical trials included thromboembolic events, myocardial infarction, and congestive heart failure in up to 0.3% of patients with CV risk factors. The incidence, outcomes, and mechanisms in real‐world clinical settings of these CV adverse effects to date have not been fully elucidated. Our study identified a patient with sipuleucel‐T‐induced inflammatory cardiomyopathy, which led to the identification of CV adverse effects associated with sipuleucel‐T from a large pharmacovigilance database and elucidation of its potential mechanisms.\n\nMethods and results\n\nUsing the MedDRA term ‘cardiac disorders’ (System Organ Class level), CV adverse events associated with sipuleucel‐T versus all other drugs were reviewed from VigiBase, a large pharmacovigilance database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator. A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. From VigiBase, the total number of CV adverse drug reaction reported with sipuleucel‐T was 306 out of a total of 22 980 104 adverse drug reactions in VigiBase on 10/25/2020. MedDRA preferred terms levels were grouped into major CV adverse drug reaction categories where we observed significant reports of myocardial ischaemia, supraventricular tachycardia (particularly atrial fibrillation/atrial flutter), congestive heart failure, and valvular disorders. Myocardial ischemia included acute myocardial infarction (IC025 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with ‘cardiac failure congestive’ (IC025 1.5), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases considered to be solely due to sipuleucel‐T.\n\nConclusions\n\nPatients with CV risk factors who are receiving sipuleucel‐T may be at higher risk for congestive heart failure, myocardial ischemia, and supraventricular tachycardia. Electrocardiograms during weekly sipuleucel‐T infusions and left ventricular function monitoring with echocardiogram should be considered in these patients. Our findings are suggestive of another rare presentation of T‐cell‐mediated CV toxicity with cancer immunotherapy.\n\nProstate cancer\nImmunotherapy\nSipuleucel‐T\nCardiomyopathy\nCardiotoxicity\nCardio‐oncology\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:28.07.2021\nMoey, M. Y. Y. , Jiwani, R. A. , Takeda, K. , Prenshaw, K. , Kreeger, R. W. , Inzerillo, J. , Liles, D. K. , Marcu, C. B. , Lebrun‐Vignes, B. , Morris, D. L. , Ardhanari, S. , and Salem, J.‐E. (2021) Sipuleucel‐T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database. ESC Heart Failure, 8 : 3360–3368. 10.1002/ehf2.13400.\n==== Body\nBackground\n\nSipuleucel‐T, marketed as Provenge®, is an autologous cellular immunological agent 1 indicated in the treatment of metastatic castration‐resistant prostate cancer (mCRPC). 2 Cardiovascular (CV) toxicities with sipuleucel‐T are uncommon (0.3%). 3 We report the first case of sipuleucel‐T‐induced inflammatory cardiomyopathy and describe the potential mechanisms. Through review of an international pharmacovigilance database, VigiBase, we also identified increased reporting of sipuleucel‐T‐associated CV toxicities.\n\nAims\n\nIn this study, we aimed to elucidate the mechanisms of sipuleucel‐T‐associated cardiomyopathy and to identify CV adverse effects associated with sipuleucel‐T in the real world from VigiBase, the World Health Organization pharmacovigilance database.\n\nClinical case\n\nA 64‐year‐old Caucasian male with well‐controlled hypertension managed with lisinopril 10 mg daily was diagnosed with mCRPC in 2018. He received two doses of subcutaneous degarelix and underwent subsequent transurethral resection of his prostate followed by 6 cycles of docetaxel 75 mg/m2 every 3 weeks along with pegfilgrastim completed 5 months later. He was initiated on enzalutamide 160 mg daily and quarterly intramuscular injections of leuprolide 40 mg shortly after. He had no complications with chemotherapy or hormonal treatment and had significant improvement with prostate‐specific antigen (PSA) < 0.1 ng/mL on subsequent follow‐up (Figure 1 ).\n\nFigure 1 Timeline of patient diagnosis and treatment of metastatic castration‐resistant prostate cancer (mCRPC) and hospitalizations. Our patient was diagnosed with stage IVB prostate cancer in fall of 2018. He was subsequently started on degarelix, which was eventually discontinued due to side effects. He received 6 cycles of docetaxel and started on enzalutamide along with leuprolide. The patient eventually received sipuleucel‐T 8 months following his initial diagnosis for mCRPC. Twenty‐four hours following his second infusion of sipuleucel‐T, he presented to the emergency department with new onset systolic dysfunction (Hospital Admission #1). He underwent coronary angiogram, which did not show obstructive disease. Cardiac magnetic resonance imaging showed late gadolinium enhancement suggestive of an infiltrative disorder. As an outpatient, he was worked up for amyloidosis, which was negative. He was discharged on lisinopril and carvedilol but presented 3 months later with recurrent symptoms and new onset atrial fibrillation (Hospital Admission #2). A myocardial biopsy was obtained during his second admission, which showed chronic myocardial inflammation. The patient was treated medically with lisinopril and carvedilol and continues to tolerate enzalutamide, leuprolide, and denosumab without any recurrent hospitalizations. ADHF, acute decompensated heart failure; AF, atrial fibrillation; HFrEF, heart failure with reduced ejection fraction; NSTEMI, non‐ST elevation myocardial infarction; Q3w, every 3 weeks; Q6 mo, every 6 months; Qd, every day/daily; SPEP, serum protein electrophoresis; SQ, subcutaneous; UPEP, urine protein electrophoresis.\n\nOn 6 months of follow‐up, he was started on sipuleucel‐T every 2 weeks for a total of three infusions. Twenty‐four hours after his second infusion of sipuleucel‐T, he presented with dyspnea and chest pressure. On physical examination, he was afebrile, blood pressure of 145/82 mmHg, and heart rate of 74 b.p.m. with an oxygen saturation of 98% on room air. He had bilateral basilar rales, jugular venous pulse noted to be at least 8 cm with a positive hepatojugular reflex, and a grade 2/6 pansystolic murmur in the apical region without any radiation. He was warm without any lower extremity edema. Electrocardiogram showed new non‐specific intraventricular conduction delay and non‐specific T wave changes in V4 to V6. Troponin I peaked at 0.80 ng/mL (normal <0.03 ng/mL). Brain natriuretic peptide was 1062 pg/mL (normal <200 pg/mL).\n\nA transthoracic echocardiogram revealed a left ventricular ejection fraction (LVEF) of 36%, grade II diastolic dysfunction, grade II mitral regurgitation due to dilated annulus, and mild aortic regurgitation. He received intravenous furosemide 40 mg daily with improvement in symptoms. Left heart catheterization showed 20% non‐obstructive disease in the left anterior descending artery, left circumflex, and right coronary artery. Cardiac magnetic resonance imaging (cMRI) showed biatrial enlargement, moderate mitral regurgitation, and a dilated left ventricular with increased myocardial mass index (116 g/m2, normal range: 42–85 g/m2) and global hypokinesis with an left ventricular ejection fraction (LVEF) of 32%. There was evidence of late gadolinium enhancement with a mottled mid‐wall pattern in the distal septum and the basal inferolateral segment, which was suggestive of a non‐ischemic cardiomyopathy representing myocardial edema or interstitial fibrosis suspicious for chemotherapy‐related cardiomyopathy or infiltrative cardiomyopathy from amyloidosis (Figure 2 ).\n\nFigure 2 Cardiac magnetic resonance imaging. (A) Three‐chamber view. Left panel (magnitude) and right (phase sensitive inversion recovery late gadolinium contrast) study demonstrating increased signal intensity in the inferolateral and distal septal regions. (B) Short‐axis view. There is mottled increased signal intensity on phase sensitive inversion recovery sequence in the distal septal area.\n\nThe patient was discharged with a LifeVest and guideline‐directed medical therapy for heart failure (HF) with reduced ejection fraction, which included carvedilol 3.125 mg twice a day and lisinopril 20 mg daily with follow‐up in the Cardio‐Oncology clinic. The patient received his last sipuleucel‐T infusion 4 weeks after discharge. During this time, given the concern for cardiac amyloidosis based on cMRI, he was worked up as an outpatient with negative fat pad biopsy, bone marrow biopsy, and urine protein electrophoresis. Serum protein electrophoresis showed elevated serum kappa light chains however with normal kappa to lambda ratio. A nuclear study based on transthyretin protein protocol performed was equivocal for cardiac amyloidosis. He presented 4 months later with a 2 week history of orthopnea found to have new‐onset atrial fibrillation and in acute decompensated HF.\n\nAn endomyocardial biopsy (EMB) was subsequently performed due to recurrent HF admission and concern for amyloidosis. The EMB showed several foci of predominant lymphocytic inflammation (Figure 3 ). Given possible immunotherapy‐related myocarditis as observed with immune checkpoint inhibitors (ICIs), 4 specific staining for T‐cell subtypes CD4+ and CD8+ was obtained in addition to a non‐standard of care stain for programmed cell death ligand‐1 (PD‐L1), which is overexpressed in ICI‐related myocarditis. 4 Cardiac amyloidosis was also evaluated with Congo red. Haematoxylin and eosin staining showed several foci of mature lymphocytic infiltration (Figure 3 A and 3 B ) that were positive for both CD4+ and CD8+ (Figure 3 D – 3 F ). PD‐L1 was not detected (Figure 3 F ). Congo red was negative (Figure 3 C ). He was discharged on carvedilol 6.125 mg twice a day, lisinopril 20 mg daily, furosemide 20 mg daily, and apixaban 5 mg twice a day. He did not have any recurrent hospitalizations. A repeat echocardiogram 1 month later showed persistent LVEF depression with an improvement to 45–50% at 6 months of follow‐up.\n\nFigure 3 Endomyocardial biopsy of the right ventricular septum. (A) Haematoxylin and eosin staining of myocardium (low magnification) showing several foci of lymphocyte infiltration. Scale bar, 100 μm. (B) Haematoxylin and eosin staining (high magnification) showing small mature lymphocytes infiltrating in the interstitial area. Scale bar, 50 μm. (C) Congo red staining showing no amyloid deposition. Inset: positive control. Scale bar, 50 μm. (D–F) Immunohistochemistry for CD4 (D), CD8 (E), and programmed cell death ligand‐1 (F). Infiltrating lymphocytes are positive for CD4 or CD8, and negative for programmed cell death ligand‐1. Scale bar, 50 μm.\n\nMethods\n\nWe searched for adverse drug reactions (ADRs) reported in VigiBase (NCT03530215), the World Health Organization database containing individual case safety reports from more than 130 countries since 1967. 5 VigiBase is managed by the Uppsala Monitoring Centre (Uppsala, Sweden). The use of confidential, electronically processed patient data was approved by the French National Commission for Data Protection and Liberties (Commission Nationale de l'Informatique et des Libertés; reference number 1922081). Using the MedDRA term ‘cardiac disorders’ (System Organ Class level), we searched for CV adverse events associated with sipuleucel‐T versus all other drugs in the database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator, which has been previously described. 6 A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. To identify the co‐occurrence of relevant CV‐ADR associated with sipuleucel‐T (IC025 > 0), individual extracted cases were reviewed and the UpSet technique 7 was used to visualize set intersections.\n\nResults\n\nThe total number of CV‐ADR reported with sipuleucel‐T versus all other drugs was 306 and 22 980 104, respectively, on 10/25/2020. There were 18 MedDRA terms of ‘cardiac disorders’ associated with sipuleucel‐T (positive IC025 > 0) (Table 1 ). MedDRA preferred terms levels were grouped into major CV‐ADR categories where there were significant reports of myocardial ischemia, supraventricular tachycardias (SVTs) (atrial fibrillation/atrial flutter), congestive HF (CHF), and valvular disorders. All of these CV‐ADRs were considered severe. Myocardial ischemia included acute myocardial infarction (IC025 = 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with ‘cardiac failure congestive’ (IC025 = 1.4), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases suspected to be solely due to sipuleucel‐T. Other CV‐ADRs were not significantly associated with sipuleucel‐T (Table 1 ). Among the major CV‐ADR categories, these occurred independently with minimal overlap among each major CV‐ADR category. Myocardial ischemia occurred independently in 84.4% (n = 65/77) of all cases, SVT 77.2% (n = 44/57), CHF 75% (n = 36/48), and valvular disorders 62.5% (n = 5/8). SVT was rarely associated with CHF (n = 6/48, 12.5%) and myocardial infarction (n = 6/77, 7.79%) (Figure 4 ).\n\nTable 1 Cardiovascular adverse events (detected as individual case safety reports) reported with sipuleucel‐T in comparison with the full VigiBase database on 10/25/2020\n\nCardiac adverse event\tMedDRA preferred term level\tICSR with sipuleucel‐T (n total = 3943)\tICSR in full database (n = 22 980 104)\tIC (IC025)\tSerious adverse events\tFatal events\tSuspected due to sipuleucel‐T only\t\nMyocardial ischaemia\tAcute myocardial infarction\t26\t17 700\t2.9 (2.3)\t26\t4\t23\t\nCoronary artery occlusion\t8\t9723\t2.0 (0.8)\t8\t2\t7\t\nMyocardial infarction\t42\t143 746\t0.8 (0.3)\t42\t13\t42\t\nCoronary artery disease\t10\t25 890\t1.1 (0.1)\t10\t0\t9\t\nSupraventricular tachycardia\tAtrial fibrillation\t49\t60 507\t2.2 (1.8)\t48\t10\t41\t\nAtrial flutter\t6\t5136\t2.2 (0.9)\t6\t1\t5\t\nCongestive heart failure\tCardiac failure congestive\t43\t67 656\t1.8 (1.4)\t43\t11\t42\t\nDilatation ventricular\t4\t1161\t2.7 (0.9)\t4\t1\t3\t\nDiastolic dysfunction\t4\t1531\t2.6 (0.8)\t4\t0\t3\t\nValvular disorders\tTricuspid valve incompetence\t5\t5017\t2.0 (0.5)\t5\t1\t5\t\nMitral valve incompetence\t6\t9522\t1.6 (0.2)\t6\t1\t4\t\nMiscellaneous\tExtrasystoles\t7\t8639\t1.9 (0.7)\t6\t0\t5\t\nTachycardia\t50\t137 211\t1.1 (0.6)\t36\t4\t44\t\nVentricular extrasystoles\t6\t7010\t1.9 (0.6)\t6\t1\t6\t\nLeft ventricular hypertrophy\t4\t2659\t2.2 (0.5)\t4\t1\t4\t\nCardiac disorder\t20\t55 766\t1.0 (0.3)\t9\t4\t20\t\nCardiomegaly\t6\t8828\t1.7 (0.3)\t6\t0\t4\t\nSinus tachycardia\t6\t9899\t1.6 (0.2)\t6\t1\t4\t\nIC, information component; ICSR, individual case safety report.\n\nAn IC025 > 0 (information component 95% credibility interval lower end) is considered significant.\n\nFigure 4 Intersection of major cardiovascular adverse drug reaction (CV‐ADR) categories associated with sipuleucel‐T. Myocardial ischemia occurred independently 84.4% (n = 65/77) of all cases, supraventricular tachycardia (SVT) 77.2% (n = 44/57), congestive heart failure (CHF) 75% (n = 36/48), and valvular disorders 62.5% (n = 5/8). SVT was rarely associated with CHF (n = 6/48, 12.5%) and myocardial infarction (n = 6/77, 7.79%).\n\nDiscussion\n\nWe describe the first reported phenomenon of a T‐cell‐mediated sipuleucel‐T‐induced cardiomyopathy. This is further corroborated by our pharmacovigilance analysis that revealed an over‐reporting of CHF with sipuleucel‐T with ~15% fatality.\n\nAlthough CV toxicities from sipuleucel‐T were uncommon among clinical trials, 3 we demonstrate through VigiBase that there was significant over‐reporting of myocardial ischemia, SVT, and CHF with sipuleucel‐T versus all other drugs. While reports from VigiBase are non‐homogeneous with the inability to definitively verify the cases with clinical, laboratory, or radiological tests, we suspect that these CV‐ADRs may have been one of the manifestations of an inflammatory‐mediated cardiomyopathy. 8 Our observation of lymphocytic inflammation on myocardial biopsy suggests that sipuleucel‐T invoked an inflammatory cascade that resulted in a T‐cell‐mediated cardiomyopathy with similar features to observed cases of immune‐related CV toxicities such as with influenza vaccination 9 , 10 and ICIs. 4\n\nIn fact, preclinical production studies of sipuleucel‐T demonstrated an immune priming response followed by immune boosting with subsequent infusions, similar to classic vaccine‐mediated cellular and humoral responses. 11 Antigen‐presenting cells, detected by CD54, were significantly up‐regulated after the first dose with the most robust response at week 4, along with antigen‐presenting cell activation‐associated cytokines, which is followed by T‐cell activation‐associated cytokines in the second and third infusion preparations. 11 Particularly, from peripheral blood samples obtained from patients receiving sipuleucel‐T, both T‐cell helper 1 (interferon and tumour necrosis factor‐α) and 2 [interleukin (IL)‐5 and IL‐13]‐specific cytokines were elevated, supporting the mechanism of sipuleucel‐T‐mediated cellular and humoral responses. Acting in concert with interferon and tumour necrosis factor‐α, an increase in IL‐17 levels was also observed, which has been implicated in the pathophysiology of autoimmune diseases. 12 Specific responses measured by anti‐PA2024 and anti‐PAP antibody titres were sustained at least until week 26. 11 This may have resulted in cytokine cascade, 9 , 10 which resulted in T‐cell recruitment and myocardial injury in our patient.\n\nUnique to our case was the observation of CD4+ and CD8+ T cells within focal inflammatory areas on myocardial biopsy. Notably, sipuleucel‐T increases the frequency of CD4+ and CD8+ T cells within prostate tissue 2 to 3 weeks after treatment, particularly at the tumour margin. 13 Whether sipuleucel‐T may induce a generalized inflammatory response that can affect additional organs has not yet been reported in preclinical sipuleucel‐T‐treated animal models. 13 These preclinical findings of an increased immune response at week 2 with the most robust response at week 4 are consistent with the timeline to development of our patient's inflammatory cardiomyopathy, further corroborating the high likelihood of sipuleucel‐T exposure as the suspected cause.\n\nWe did not observe an increased expression of PD‐L1 in the myocardium as previously demonstrated in ICI‐related myocarditis. 4 This is likely due to a variation in the mechanism of action whereby ICI exhibits a generalized immune blockade whereas sipuleucel‐T induces a destruction specific to prostate cancer cells. However, the phenomenon of ‘antigen spread’ with sipuleucel‐T where additional prostate cancer‐associated tumour antigens involved in PSA processing and oncologic downstream signalling were targeted has also been observed. 14 We suspect that cross‐reactivity and/or shared antigen recognition within the myocardium by sipuleucel‐T is likely low, however possible in pro‐inflammatory environments such as patients with CV risk factors. 15\n\nOur patient had LVEF recovery within 6 months on guideline‐directed medical therapy only. This suggests that the immune‐mediated mechanisms were likely transient, with reversion to a balanced non‐inflammatory environment following completion of sipuleucel‐T treatment. Nonetheless, our patient experienced a severe reaction reflecting our pharmacovigilance results in which approximately 15% of patients with spiuleucel‐T‐associated CHF associated suffered fatal outcomes. While our patient was concomitantly receiving androgen‐deprivation therapy (ADT) with enzalutamide and leuprolide, the likelihood of ADT resulting in cardiomyopathy was low in the differential. Cardiotoxicities reported with ADT include cardiometabolic disturbances (hypertension, hyperglycemia, and hyperlipidemia) and risk of arrhythmias from prolonged QTc 16 and are generally not associated risk of HF; in clinical trials, HF was reported to be <1%. 17 , 18 Docetaxel has also not been associated with HF despite prolonged use. 19 Our patient tolerated ADT and docetaxel for several months but developed acute onset of symptoms with sipuleucel‐T, correlating with the timeline of the immune modulating mechanism of sipuleucel‐T and potential crosstalk between pathways making sipuleucel‐T the most plausible culprit of our patient's inflammatory cardiomyopathy.\n\nIn comparison with the familiarity of cardiotoxicities associated with anthracyclines and anti‐human epidermal growth factor receptor (HER2) therapy, prostate cancer therapy‐induced cardiac adverse events are underrecognized. There have been concerns regarding adequate reporting and potential under recognition of adverse cardiac events with prostate cancer therapies as the studies were not designed to detect cardiotoxicities. 20 Therefore, we encourage consideration of monitoring in patients with CV risk factors with serial electrocardiograms during weekly infusions and obtaining a baseline echocardiogram in patients receiving sipuleucel‐T. Additional studies investigating the complex immune‐mediated mechanisms in patients receiving immunotherapy and optimal management to avoid off‐target organ inflammation without affecting the salutary effects of immunotherapy are highly warranted.\n\nLimitations\n\nOur study is not without limitations. As there are no current guidelines regarding obtaining baseline cardiac diagnostic testing prior to initiation of prostate cancer treatment, our patient did not have a baseline echocardiogram for comparison. The patient did not have any cardiac symptoms or complaints that would have suggested baseline systolic or valvular dysfunction; therefore, it is assumed that his baseline cardiac function was normal prior to and during his non‐immunotherapy treatment for mCRPC. Another limitation of our study was the lack of viral genome data from EMB. The patient did not have any viral or infectious symptoms at the time of his admission in addition to negative blood cultures and respiratory viral panel; an infectious or viral‐associated cardiomyopathy was very low in the differential. In addition, limitations with VigiBase reporting are voluntary, and thus, not all data fields are included in every report, and quality might be variable.\n\nConflict of interest\n\nNone declared.\n\nSupporting information\n\nFigure S1. Supporting Information.\n\nClick here for additional data file.\n\nFigure S2. Supporting Information.\n\nClick here for additional data file.\n\nAcknowledgements\n\nThe supplied data from VigiBase® come from various sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the World Health Organization.\n==== Refs\nReferences\n\n1 Cheever M , Higano C . PROVENGE (sipuleucel‐T) in prostate cancer: the first FDA‐approved therapeutic cancer vaccine. Clin Cancer Res 2011; 17 : 3520–3526.21471425\n2 Kantoff PW , Higano CS , Shore ND , Berger ER , Small EJ , Penson DF , Redfern CH , Ferrari AC , Dreicer R , Sims RB , Xu Y , Frohlich MW , Schellhammer PF . Sipuleucel‐T immunotherapy for castration‐resistant prostate cancer. N Engl J Med 2010; 363 : 411–422.20818862\n3 Higano CS , Armstrong AJ , Sartor AO , Vogelzang NJ , Kantoff PW , McLeod DG , Pieczonka CM , Penson DF , Shore ND , Vacirca J , Concepcion RS , Tutrone RF , Nordquist LT , Quinn DI , Kassabian V , Scholz MC , Harmon M , Tyler RC , Chang NN , Tang H , Cooperberg MR . Real‐world outcomes of sipuleucel‐T treatment in PROCEED, a prospective registry of men with metastatic castration‐resistant prostate cancer. Cancer 2019; 125 : 4172–4180.31483485\n4 Johnson DB , Balko JM , Compton ML , Chalkias S , Gorham J , Xu Y , Hicks M , Puzanov I , Alexander MR , Bloomer TL , Becker JR , Slosky DA , Phillips EJ , Pilkinton MA , Craig‐Owens L , Kola N , Plautz G , Reshef DS , Deutsch JS , Deering RP , Olenchock BA , Lichtman AH , Roden DM , Seidman CE , Koralnik IJ , Seidman JG , Hoffman RD , Taube JM , Diaz LA Jr , Anders RA , Sosman JA , Moslehi JJ . Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016; 375 : 1749–1755.27806233\n5 Lindquist M . VigiBase, the WHO global ICSR database system: basic facts. Drug Inf J 2008; 42 : 409–419.\n6 Salem JE , Manouchehri A , Moey M , Lebrun‐Vignes B , Bastarache L , Pariente A , Gobert A , Spano JP , Balko JM , Bonaca MP , Roden DM , Johnson DB , Moslehi JJ . Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018; 19 : 1579–1589.30442497\n7 Lex A , Gehlenborg N , Strobelt H , Vuillemot R , Pfister H . UpSet: visualization of intersecting sets. IEEE Trans Vis Comput Graph 2014; 20 : 1983–1992.26356912\n8 Lyon AR , Yousaf N , Battisti NML , Moslehi J , Larkin J . Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol 2018; 19 : e447–e458.30191849\n9 Saraiya N , Singh S , Corpuz M . Fatal influenza myocarditis with incessant ventricular tachycardia. BMJ Case Rep CP 2019; 12 : e228201.\n10 Kim YJ , Bae JI , Ryoo SM , Kim WY . Acute fulminant myocarditis following influenza vaccination requiring extracorporeal membrane oxygenation. Acute Crit Care 2019; 34 : 165–169.31723923\n11 Sheikh NA , Petrylak D , Kantoff PW , dela Rosa C , Stewart FP , Kuan LY , Whitmore JB , Trager JB , Poehlein CH , Frohlich MW , Urdal DL . Sipuleucel‐T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration‐resistant prostate cancer. Cancer Immunol Immunother 2013; 62 : 137–147.22865266\n12 Kuwabara T , Ishikawa F , Kondo M , Kakiuchi T . The role of IL‐17 and related cytokines in inflammatory autoimmune diseases. Mediators Inflamm 2017; 2017 : 3908061.28316374\n13 Laus R , Yang DM , Ruegg CL , Shapero MH , Slagle PH , Small EJ , Burch P , Valone FH . Dendritic cell immunotherapy of prostate cancer: preclinical models and early clinical experience. Cancer Res Ther Control 2001; 11 : 1–10.\n14 GuhaThakurta D , Sheikh NA , Fan LQ , Kandadi H , Meagher TC , Hall SJ , Kantoff PW , Higano CS , Small EJ , Gardner TA , Bailey K , Vu T , DeVries T , Whitmore JB , Frohlich MW , Trager JB , Drake CG . Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel‐T and its association with improved clinical outcome. Clin Cancer Res 2015; 21 : 3619–3630.25649018\n15 Willerson JT , Ridker PM . Inflammation as a cardiovascular risk factor. Circulation 2004; 109 : II2–II10.15173056\n16 Salem JE , Yang T , Moslehi JJ , Waintraub X , Gandjbakhch E , Bachelot A , Hidden‐Lucet F , Hulot JS , Knollmann BC , Lebrun‐Vignes B , Funck‐Brentano C , Glazer AM , Roden DM . Androgenic effects on ventricular repolarization: a translational study from the international pharmacovigilance database to iPSC‐cardiomyocytes. Circulation 2019; 140 : 1070–1080.31378084\n17 Scher HI , Fizazi K , Saad F , Taplin ME , Sternberg CN , Miller K , de Wit R , Mulders P , Chi KN , Shore ND , Armstrong AJ , Flaig TW , Fléchon A , Mainwaring P , Fleming M , Hainsworth JD , Hirmand M , Selby B , Seely L , de Bono JS . Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367 : 1187–1197.22894553\n18 Beer TM , Armstrong AJ , Rathkopf DE , Loriot Y , Sternberg CN , Higano CS , Iversen P , Bhattacharya S , Carles J , Chowdhury S , Davis ID . Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371 : 424–433.24881730\n19 Zamorano JL , Lancellotti P , Rodriguez Muñoz D , Aboyans V , Asteggiano R , Galderisi M , Habib G , Lenihan DJ , Lip GYH , Lyon AR , Fernandez TL , Mohty D , Piepoli MF , Tamargo J , Torbicki A , Suter TM , ESC Scientific Document Group . 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37 : 2768–2801.27567406\n20 Witteles RM , Telli M . Underestimating cardiac toxicity in cancer trials: lessons learned? J Clin Oncol 2012; 30 : 1916–1918.22454419\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2055-5822", "issue": "8(4)", "journal": "ESC heart failure", "keywords": "Cardio-oncology; Cardiomyopathy; Cardiotoxicity; Immunotherapy; Prostate cancer; Sipuleucel-T", "medline_ta": "ESC Heart Fail", "mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D001499:Bayes Theorem; D006801:Humans; D009205:Myocarditis; D060735:Pharmacovigilance; D014020:Tissue Extracts", "nlm_unique_id": "101669191", "other_id": null, "pages": "3360-3368", "pmc": null, "pmid": "33938158", "pubdate": "2021-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25649018;15173056;28316374;31483485;22454419;27806233;31266755;22865266;26356912;21471425;30442497;30191849;31378084;27567406;24881730;33938158;22894553;31723923;20818862", "title": "Sipuleucel-T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database.", "title_normalized": "sipuleucel t associated inflammatory cardiomyopathy a case report and observations from a large pharmacovigilance database" }

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{ "abstract": "We report a case of breast cancer in a 58-year-old female patient. In 2005, she was hospitalized for therapy of left breast cancer. The tumor observed was accompanied by invasion of the skin and ribs. At the same time, multiple liver and bone metastases were also observed(solid tubular adenocarcinoma, ER(+), PgR(±), HER2(3+), T4NxM1, stage IV). She was started on radiation therapy and chemotherapy(paclitaxel+trastuzumab). While the liver and bone metastases remained unchanged, the primary focus became noticeably smaller. In the course of follow-up visits, we began to administer her paclitaxel biweekly. This treatment, however, worsened her liver metastases and led us to switch to combination chemotherapy with vinorelbine and capecitabine. After 6 courses of the therapy, her liver metastases disappeared and her tumor marker levels became normal. The combination chemotherapy was continued for 1 year and then followed by 18 months of chemotherapy with capecitabine alone until recurrence of liver metastases was observed. Capecitabine along with cyclophosphamide was orally administered, bringing her tumor marker levels down to the normal range again. After approximately 6 years from the start of treatment, the patient is still alive.", "affiliations": "Dept. of Surgery, Takarazuka City Hospital, Japan.", "authors": "Yamazaki|Junya|J|;Kou|Toshimori|T|;Sakakura|Chohei|C|;Oguro|Atsushi|A|;Nakagawa|Noboru|N|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "39(3)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D001706:Biopsy; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008875:Middle Aged; D012074:Remission Induction; D014456:Ulcer", "nlm_unique_id": "7810034", "other_id": null, "pages": "437-9", "pmc": null, "pmid": "22421775", "pubdate": "2012-03", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy.", "title_normalized": "a case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy" }

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A CASE OF BREAST CANCER WITH LARGE CANCER ULCER AND MULTIPLE BONE AND LIVER METASTASIS RESPONDING TO COMBINATION THERAPY OF RADIATION AND CHEMOTHERAPY.. 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"reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAMAZAKI J, KOU T, SAKAKURA C, OGURO A, NAKAGAWA N. A CASE OF BREAST CANCER WITH LARGE CANCER ULCER AND MULTIPLE BONE AND LIVER METASTASIS RESPONDING TO COMBINATION THERAPY OF RADIATION AND CHEMOTHERAPY. GAN-TO-KAGAKU-RYOHO. 2012;39 (3):437-439", "literaturereference_normalized": "a case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160415", "receivedate": "20160415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12271536, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-FRESENIUS KABI-FK201601538", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077574", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077574", "drugbatchnumb": "UNKNOWN", 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"patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to liver", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAMAZAKI J,KOU T,SAKAKURA C,OGURO A,NAKAGAWA N. A CASE OF BREAST CANCER WITH LARGE CANCER ULCER AND MULTIPLE BONE AND LIVER METASTASIS RESPONDING TO COMBINATION THERAPY OF RADIATION AND CHEMOTHERAPY. GAN-TO-KAGAKU-RYOHO 2012?39 (3):437-439.", "literaturereference_normalized": "a case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160330", "receivedate": "20160330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12222279, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "JP-MYLANLABS-2016M1011617", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091540", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "BIWEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to liver", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YAMAZAKI J, KOU T, SAKAKURA C, OGURO A, NAKAGAWA N. A CASE OF BREAST CANCER WITH LARGE CANCER ULCER AND MULTIPLE BONE AND LIVER METASTASIS RESPONDING TO COMBINATION THERAPY OF RADIATION AND CHEMOTHERAPY. [JAPANESE]. GAN-TO-KAGAKU-RYOHO 2012?39(3):437-439.", "literaturereference_normalized": "a case of breast cancer with large cancer ulcer and multiple bone and liver metastasis responding to combination therapy of radiation and chemotherapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12191981, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "BACKGROUND\nCancer is the second leading cause of death of women during the reproductive years, and its occurrence in pregnancy is between 0.07% and 0.1%.\n\n\nMETHODS\nTo analyze the effect of cancer on pregnancy, we compared 21 pregnancies occurring during 30 years in women who received chemotherapy for their cancer with a control group matched for maternal age and composed of women not exposed to known teratogens or reproductive risks during pregnancy.\n\n\nRESULTS\nOf 13 women exposed to chemotherapy during the first trimester, two of five whose pregnancies continued to term had major malformations in their infants, four had spontaneous abortions, and four had therapeutic abortions. Of four women with second-trimester exposure to chemotherapy, two had normal live births, one had a stillbirth, and one had a therapeutic abortion. All four pregnancies exposed to chemotherapy during the third trimester resulted in healthy live births. Infants exposed to chemotherapy had statistically significantly lower birth weights than their matched controls (2227 +/- 558 g vs 3519 +/- 272 g, P less than .001), due to both significantly lower gestational age and substantial intrauterine growth retardation (P less than .01). The trend for higher rate of stillbirth (1/11) agrees well with 10 stillbirths among all women with cancer in pregnancy without and with chemotherapy who gave birth (n = 223), when compared with the population of Ontario (P less than .0005).\n\n\nCONCLUSIONS\nThis study confirms the increased likelihood of spontaneous abortions and major birth defects when chemotherapy is used during embryogenesis, whereas such a risk is not apparent beyond the first trimester. Because of the higher risk of stillbirth and intrauterine growth retardation, women with cancer should be monitored closely by a high-risk obstetric unit to define the optimal time of delivery.", "affiliations": "Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.", "authors": "Zemlickis|D|D|;Lishner|M|M|;Degendorfer|P|P|;Panzarella|T|T|;Sutcliffe|S B|SB|;Koren|G|G|", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-9926", "issue": "152(3)", "journal": "Archives of internal medicine", "keywords": null, "medline_ta": "Arch Intern Med", "mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D000013:Congenital Abnormalities; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D009864:Ontario; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third", "nlm_unique_id": "0372440", "other_id": null, "pages": "573-6", "pmc": null, "pmid": "1546920", "pubdate": "1992-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Fetal outcome after in utero exposure to cancer chemotherapy.", "title_normalized": "fetal outcome after in utero exposure to cancer chemotherapy" }

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ARCH INTERN MED. 1992?152:573-576", "literaturereference_normalized": "fetal outcome after in utero exposure to cancer chemotherapy", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190708", "receivedate": "20190708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16541216, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-ORION CORPORATION ORION PHARMA-TREX2019-2158", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "042", 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-LEFLUNOMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rheumatoid arthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FETAL OUTCOME AFTER IN UTERO EXPOSURE TO CANCER CHEMOTHERAPY.", "literaturereference_normalized": "fetal outcome after in utero exposure to cancer chemotherapy", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190703", "receivedate": "20190703", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16521596, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "CA-PFIZER INC-2019281857", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROCARBAZINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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FETAL OUTCOME AFTER IN UTERO EXPOSURE TO CANCER CHEMOTHERAPY. ARCH INTERN MED. 1992?152:573-576", "literaturereference_normalized": "fetal outcome after in utero exposure to cancer chemotherapy", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190708", "receivedate": "20190708", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16541085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "CA-PFIZER INC-2019281855", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROCARBAZINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROCARBAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MECHLORETHAMINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MECHLORETHAMINE HYDROCHLORIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HODGKIN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abortion spontaneous", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZEMLICKIS, D.. 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{ "abstract": "BACKGROUND\nDementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65 years and above. More effective ways to manage dementia symptoms are needed because current treatment options (antidepressants and antipsychotics) can be ineffective and are associated with substantial side effects, including increased rate of mortality. Cannabinoid-based medicine (CBM) has shown an ability to inhibit some symptoms associated with dementia, and the adverse effects are often minimal; yet, little research has explored the use of CBM among this population.\n\n\nOBJECTIVE\nTo monitor the safety of a purified dose of CBM oil (3:2 delta-9-tetrahydrocannabinol:cannabidiol) on behaviour symptoms, quality of life and discomfort caused by pain.\n\n\nMETHODS\nWe will carry out an 18-week, randomised, double-blind crossover trial that consists of a 2-week eligibility period, two 6-week treatment cycles, and two 2-week washout periods (between both cycles and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups and will receive a dose of either CBM oil or placebo for the first treatment cycle and the opposite medication for the second. Data will be collected using the Neuropsychiatric Inventory Questionnaire, the Cohen-Mansfield Agitation Inventory, the Quality of Life in Alzheimer's Disease questionnaire, and the Abbey Pain Scale on seven occasions. These will be completed by the participants, aged-care staff, and nominated next of kin or family members. The participants' heart rate and blood pressure will be monitored weekly, and their body composition and weight will be monitored fortnightly by a research nurse, to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions of CBM and to inform proposed focus groups consisting of the aged-care staff and next of kin.\n\n\nCONCLUSIONS\nThe study design has been informed by medical professionals and key stakeholders, including those working in the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.\n\n\nBACKGROUND\nAustralian New Zealand Clinical Trials Registry, ACTRN12619000474156. Registered on 21 March 2019.", "affiliations": "Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia. [email protected].;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.;Emerald Clinics, Perth, WA, Australia.;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.;Institute for Health Research, University of Notre Dame Australia, Perth, WA, Australia.", "authors": "Timler|Amanda|A|http://orcid.org/0000-0003-2619-5937;Bulsara|Caroline|C|;Bulsara|Max|M|;Vickery|Alistair|A|;Smith|Jill|J|;Codde|Jim|J|", "chemical_list": "D002186:Cannabinoids; D064086:Medical Marijuana; D010938:Plant Oils", "country": "England", "delete": false, "doi": "10.1186/s13063-020-4085-x", "fulltext": "\n==== Front\nTrialsTrialsTrials1745-6215BioMed Central London 408510.1186/s13063-020-4085-xStudy ProtocolUse of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial http://orcid.org/0000-0003-2619-5937Timler Amanda [email protected] 1Bulsara Caroline 1Bulsara Max 1Vickery Alistair 2Smith Jill 1Codde Jim 11 0000 0004 0402 6494grid.266886.4Institute for Health Research, University of Notre Dame Australia, Perth, WA Australia 2 Emerald Clinics, Perth, WA Australia 14 2 2020 14 2 2020 2020 21 18816 5 2019 18 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDementia is a neurological condition that affects the cognitive and functional ability of the brain and is the leading cause of disability among those aged 65 years and above. More effective ways to manage dementia symptoms are needed because current treatment options (antidepressants and antipsychotics) can be ineffective and are associated with substantial side effects, including increased rate of mortality. Cannabinoid-based medicine (CBM) has shown an ability to inhibit some symptoms associated with dementia, and the adverse effects are often minimal; yet, little research has explored the use of CBM among this population.\n\nAim\nTo monitor the safety of a purified dose of CBM oil (3:2 delta-9-tetrahydrocannabinol:cannabidiol) on behaviour symptoms, quality of life and discomfort caused by pain.\n\nMethods/design\nWe will carry out an 18-week, randomised, double-blind crossover trial that consists of a 2-week eligibility period, two 6-week treatment cycles, and two 2-week washout periods (between both cycles and after the second treatment cycle). We aim to recruit 50 participants with dementia who are living in residential aged-care facilities. The participants will be randomised into two groups and will receive a dose of either CBM oil or placebo for the first treatment cycle and the opposite medication for the second. Data will be collected using the Neuropsychiatric Inventory Questionnaire, the Cohen-Mansfield Agitation Inventory, the Quality of Life in Alzheimer’s Disease questionnaire, and the Abbey Pain Scale on seven occasions. These will be completed by the participants, aged-care staff, and nominated next of kin or family members. The participants’ heart rate and blood pressure will be monitored weekly, and their body composition and weight will be monitored fortnightly by a research nurse, to assess individual dose response and frailty. In addition, pre- and post-surveys will be administered to aged-care staff and family members to understand their perceptions of CBM and to inform proposed focus groups consisting of the aged-care staff and next of kin.\n\nDiscussion\nThe study design has been informed by medical professionals and key stakeholders, including those working in the residential aged-care industry to ensure patient safety, collection of non-invasive measures, and methodological rigor and study feasibility.\n\nTrial registration\nAustralian New Zealand Clinical Trials Registry, ACTRN12619000474156. Registered on 21 March 2019\n\nKeywords\nDementiaMedicinal cannabisQuality of lifePainBehavioural and neuropsychiatric symptoms of dementia (BPSD)Crossover trialMGC Pharmaceuticals issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDementia is a collection of symptoms that progressively reduces the cognitive and functional ability of the brain [1] and affects memory, intellect, rationality, social skills and physical functioning [2]. The symptoms associated with dementia present themselves in a variety of ways and can include depression, frustration, clinginess, forgetfulness, wandering, sexual aggression, hoarding, sleep disturbances and ‘the sundowner effect’ (increased manifestations of challenging behaviours at the end of the day [3]). Severe cognitive fluctuations in patients with dementia have been associated with an individual’s impaired ability to engage in activities of daily living, including social interactions and poorer quality of life (QOL) [4]. The slow progression and degeneration of dementia require that the affected individual receive additional support and assistance to remain at home or ultimately admission into residential aged-care facilities with 24-h care.\n\nDementia is the second leading burden of disability among Australians aged 65 years and older, and the burden of disease is expected to increase exponentially over the next 30 years [5]. Alzheimer’s disease is the most common cause of dementia and affects approximately 50–70% of the elderly with dementia. Pharmacological management of behavioural and physical symptoms of dementia is currently the most common treatment option, and many are prescribed medications such as off-label antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, and antidepressants to mask and alleviate the array of dementia symptoms [6, 7]. Medications such as aripiprazole, olanzapine, risperidone and memantine have been shown to reduce troublesome behaviours [8], although unclear guidelines are often provided for administration [2, 7]. This results in polypharmacy and its inherent risks, with numerous medications being prescribed for a longer duration than recommended [9]. Many of these medications lead to a number of substantial side effects [10], including increased rate of stroke and mortality [11].\n\nCannabinoid-based medicines (CBMs) have been shown to improve dementia symptoms such as aggression and agitation [12, 13], and they appear to be safer to prescribe than other pharmacotherapies [3] because the adverse effects are often minimal [14]. For example, Weier and Hall [15] found sedation to be the only adverse effect among patients with dementia prescribed either cannabinoids or pharmacotherapies. While periods of euphoria, somnolence and tiredness were observed among those prescribed dronabinol, a synthetically derived delta-9-tetrahydrocannabinol (THC) [16], there were only a small number of adverse events (6 of 98) related to the administration of the synthetic THC similar to those manifested by the placebo [14, 17]. However, well-designed, randomised, double-blind, placebo-controlled trials need to be completed to understand the most efficacious formulation, safety profile, drug–drug interactions and true effect to determine the place of CBM in dementia [18, 19], allowing greater generalisability of these outcomes [20].\n\nA range of CBMs (synthetic compounds such as dronabinol or nabilone or pure cannabinols) are available; however, the combination of cannabidiol (CBD; the non-psychoactive compound) and THC (the psychoactive compound) [21] appear to be most effective, because both compounds improve psychomotor activity, mood, sleep–wake cycles and eating behaviours [14, 22, 23]. THC and CBD interact with the endogenous cannabinoid systems CB1 and CB2 receptors [19, 23, 24], producing symbiotic neuroprotective effects. For example, in pre-clinical trials, THC is found to be a partial CB1 antagonist and improves immune function [25], encourages amyloidogenesis [14, 22, 23, 26, 27], reduces neuropsychiatric symptoms, reduces pain sensation [28], stimulates appetite [21–23, 29], and inhibits acetylcholinesterase, similarly to cholinesterase inhibitors such as donepezil [30]. CBD is an inverse CB1 agonist [31] that promotes neurogenesis and vasodilation within the brain; increases neuronal plasticity and cerebral blood flow [32]; prevents cell destruction; and has anti-inflammatory (neuroinflammation and peripheral inflammation), analgesic, anticonvulsant and anxiolytic properties [25]. CBD is an important compound because it reverses the negative cognitive consequences and ameliorates the psychoactive properties of THC [21–23, 29].\n\nStudies assessing the safety and efficiency of CBMs have shown many benefits among other neurodegenerative diseases, such as Parkinson’s disease [33, 34], epilepsy, post-traumatic stress disorder [18, 35], anxiety [12], and spasticity due to multiple sclerosis [36], with the use of CBM reducing benzodiazepine prescriptions by 45% [37]. However, only a handful of studies have investigated the use of CBM in patients with dementia [13, 14, 23]. Recently, an observational study monitored the use of a CBM medication over a 2-month period among ten females with severe dementia and found a 40% reduction in behavioural problems and 50% reduction in rigidity [38].\n\nThe pharmacodynamics and pharmacokinetics of THC (weeks 1–6, 0.75 mg; weeks 7–12, 1.5 mg) administered to ten participants with dementia was safe and well tolerated [14]. Administration of THC 2.5 mg in 11 patients with dementia demonstrated positive effects on mental state; dementia severity; and behavioural symptoms such as delusions, irritability, sleep and caregiver distress [23]. Studies reporting the use of dronabinol (2.5 mg daily) found improvements in anorexia and body weight, as well as less disturbed behaviours [16] such as agitation and motor behaviours, with no adverse effects observed [39]. Retrospective observations of dronabinol administration among 40 hospitalised patients indicated improvements in agitation and aggression, sleep duration, and meal consumption [13]. Two independent case studies monitoring the effects of nabilone (maximum dose 0.5 mg twice daily for 6 weeks) among elders with dementia found improvements in severe agitation and aggression [40], psychomotor activity, and smiling, as well as positive experiences among family members [41]. No changes in the number of falls or in balance (with eyes open) were reported among 18 participants administered 1.5 mg of oral THC twice daily [42], with recommendations suggesting higher doses (THC 1.5 mg three times daily), and longer study durations (great than 3 weeks) are needed to understand the true effects on behavioural symptoms, including QOL and activities of daily living [43]. Therefore, further research in this area is needed because many beneficial outcomes have been reported, although dosing, samples size, patient cohort (2–50 participants) and outcomes have varied in what are generally small studies with poor experimental designs.\n\nAims\nThe primary aim of the present study will be to see if a purified CBM oil is safe and improves behavioural and neuropsychiatric symptoms of dementia (BPSD). In addition, two secondary aims of this study will include examining QOL and discomfort caused by pain among patients with dementia receiving CBM oil.\n\nMethods and general study design\nThis study has received approval from the Human Ethics Research Committee at the University of Notre Dame Australia. The study will use a parallel mixed methods design. The research methodology for this study is a phase II, randomised, placebo-controlled crossover trial. The design will include a 2-week eligibility (assessment) period, two 6-week-treatment cycles to allow each participant to take part in both the control and treatment cycles, and two 2-week washout periods (one between both treatment cycles and the other after the second treatment cycle). The 6-week treatment cycles have been selected on the basis of safety, pharmacodynamics, and pharmacokinetics as reported by Ahmed et al. [14], and a 2-week washout period has been shown to be safe and an appropriate length of time for cannabis to metabolise in older individuals [44].\n\nIn addition, residential aged-care staff and next of kin perceptions towards the use of CBM oil will be evaluated via surveys administered prior to and upon completion of the study. At the end of the second treatment cycle, the residential aged-care staff and family members will be asked to participate in a follow-up focus group to gather more in-depth information regarding individuals’ perceptions before and after the administration of CBM. Each participant will be in the trial for approximately 4 months (18 weeks), but the duration of the study will last over 12 months in order to recruit participants from a number of aged-care facilities.\n\nParticipants and setting\nParticipants will be recruited through residential aged-care facilities. Residential aged-care facilities within Australia are government-funded organisations that provide additional support for families who may have a family member with dementia, whereby many move from their residential homes into a residential aged-care facility so that they can be monitored and provided with additional care. PASS2019 power analysis and sample size software (ncss.com/software/pass; NCSS, Kaysville, UT, USA) was used to derive the sample size. The Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) is the primary outcome measure. Total sample size for a 2 × 2 crossover design assuming a two-sided t test to detect a mean difference of 6 on the NPI-NH scale with a standard deviation of 13 (for the difference) is 40 for a power of 80% and significance level of 5%. Fifty participants will be recruited to allow for a 20% attrition rate. Participants will be eligible to participate if they live in a residential aged-care facility, are aged 65 years or older, have a diagnosis of mild dementia (indicated by a score ≥ 20 on the Mini Mental State Examination [MMSE]), are able to speak English, are known as compliant with taking medication, are not bedridden, and are able to provide informed consent. Participants will be excluded if they have certain health conditions, such as frontotemporal or Lewy body dementia; have other comorbidities, such as epilepsy, anorexia nervosa, comorbid psychiatric conditions, Parkinson’s disease, or congestive heart failure; have a history of myocardial infarction or anginal pain, stroke, liver disease, or renal disease; or are taking medications such as primidone, phenobarbital, carbamazepine, rifampicin, rifabutin, troglitazone, Hypericum perforatum, and valproic acid that may interact with cannabis metabolism.\n\nThe pre-/post-surveys and focus group discussions are an exploratory, qualitative component of this study, and thus a definitive sample size calculation cannot be determined at this stage. We estimate that six focus groups comprising six to eight participants, including two groups of residential care staff, activity staff (care staff who monitor daily activities and social engagement), and family members, will ensure that data saturation has been reached. Written informed consent will be obtained from all participants, including the residential aged-care staff and the next of kin.\n\nRigor\nResidential aged-care staff usually work within the aged-care setting for at least 3 months and therefore are likely to be working in the same facility for the duration of the 4-month trial. The same aged-care staff member will monitor the same participant(s) for the duration of the study and report any changes on the participants’ behalf. To be classified as a residential care staff member, the individual must spend at least two occasions per week with the participant. The same registered nurse will administer the medication for both treatment cycles.\n\nRecruitment\nThe residential aged-care clinical and general managers who have established relationships with the participants and their next of kin will promote the study to those they feel would be eligible to participate. This will be performed through face-to-face conversations.\n\nRandomisation\nThe randomisation process for this study will be done by creating a random number list using a 1:1 ratio allocation to ensure an equal number of cases in both the placebo group (n = 25) and the treatment group (n = 25) using Excel software (Microsoft Corp., Redmond, WA, USA). The determination of participant allocation will be completed by the laboratory manager in the drug manufacturing laboratory, with each case being provided a unique identification (ID) number (1–50). The primary researcher, who is responsible for recruitment, will provide the laboratory manager with the participant’s name to be sequentially matched against with the next available ID number. The laboratory will provide the pharmacy with both CBM and placebo in identical bottles labelled with the ID, but the medical practitioner and research team members will not know the order of treatment until the completion of the study. The pharmacist will place the participant’s name on the bottle before distributing the bottles to the aged-care facilities.\n\nBlinding\nThis is a double-blind study. Therefore, the laboratory manager will be the only individual who will know the group allocation for the participants. This is to ensure that the pharmacist, aged-care staff, medical practitioners, research nurse, family members/next of kin, participants and researchers are all blinded to the participant’s group allocation. Once the study is complete, the laboratory manger will un-blind the information by providing the primary researcher with a list of participants and their group allocation in order to conduct the analysis.\n\nProcedure\nThe study will run for 18 weeks, comprising a 2-week eligibility period for screening and clinical assessment and a 16-week experimental phase encompassing two 6-week cycles of treatment and placebo separated by a 2-week washout period between the treatment cycles and a 2-week washout period following the completion of the second arm (Fig. 1).\nFig. 1 The key phases of the 18-week trial\n\n\n\nEligibility period\nIndividuals who express interest in participating in the study will initially be screened on the basis of inclusion criteria (described above). Following the initial screening process, potential participants will undergo a thorough clinical investigation by a geriatrician to ensure they have the cognitive capacity to provide informed consent using the MMSE. The MMSE [45] is the most widely used cognitive outcome measure to assess the severity of cognitive performance. It comprises 11 items, where a total score out of 30 can be calculated to assess the severity of dementia (25–30 = questionably significant, 20–25 = mild, 10–20 = moderate, 0–10 = severe). Those who seem suitable will be revisited by the geriatrician 1 week after the cognitive tests and will confirm that the participant has understood the purpose of the trial and has recalled the details of the study. Then the primary researcher will invite the eligible participants to enrol in the study and ask them to complete the consent form and provide some demographic and baseline information, including age, sex, education level, weight, medical history including comorbid illnesses, and prescribed medications. The participants will then be randomly allocated to treatment group A or B and receive either CBM oil or placebo for the first 6-week treatment cycle. No adjustments will be made to the participants’ currently prescribed medications.\n\nExperimental phase\nThis phase of the study will take 16 weeks to complete. To minimise the risk of adverse events and variation in the maximum tolerated dose of CBM oil, each participant will receive one dose on the first and second days (2 pm) and two doses (9 am and 2 pm) for the reminder of both treatment cycles. A registered nurse will administer the dose along with a small meal (e.g., morning and afternoon tea), and the rate of titration will be monitored by the pharmacist to ensure it is appropriate for each individual. The participant will gradually receive an increased dose (titration) of the medication over several weeks, as shown in Table 1. During these weeks, the participant along with the care staff will record the presence of, and any change in, any potential adverse events that may be associated with the medication after the first dose, each afternoon when the dose is increased, and again on the final day of medication. If an adverse event is noted, the participant will revert to their previous best tolerated dose using the adverse events and safety protocol listed below.\nTable 1 Titration administration, including dose and number of sprays\n\nDay(s)\tWeek\tDose administered (daily)\tNumber of spray(s) per dose\tAdverse events recorded (time)\t\n9 am\t2 pm\t\n1, 2\t1\t–\t2.5 mg\t1\t3 pm\t\n3, 4\t1\t2.5\t2.5\t1\t\t\n5, 6\t1\t2.5\t5\t1–2\t3 pm\t\n7, 8\t1\t5\t5\t2\t\t\n9, 10\t2\t5\t10\t2–4\t3 pm\t\n11, 12\t2\t10\t10\t4\t\t\n13, 14\t2\t10\t15\t4–6\t3 pm\t\n15, 16\t2/3\t15\t15\t6\t\t\n17, 18\t3\t15\t20\t6–8\t3 pm\t\n19, 20\t3\t20\t20\t8\t\t\n21, 22\t3/4\t20\t25\t8–10\t3 pm\t\n23, 24\t4\t25\t25\t10\t3 pm\t\nAdverse events will be recorded 1 h after drug administration on days of dose increase (days bolded) and on the last day of the treatment period\n\n\n\nAn upper limit of 50 mg/day of THC will be permitted in those who do not experience any adverse events from the medication. Once a participant has reached their maximum tolerated dose (or a total of 50 mg/daily of THC), they will continue to receive that dose until the cessation of the 6-week period. The placebo group will follow a similar titration process using the indicated volumes shown in Table 1. They will continue to receive an increase in the volume of medication until they record an onset of an adverse event, at which time they will continue to take that volume of placebo until the end of the 6-week placebo cycle.\n\nManagement and administration of medication\nThe CBM oil (CogniCann; MGC Pharmaceuticals Ltd., Perth, Australia) will be provided in a sealed 10-ml glass spray bottle which contains a mix of THC and CBD in a 3:2 ratio (25 mg/ml THC; 17 mg/ml CBD) in a medium-chain triglycerides oil base. Each press of the vial will accurately dispense 100 μl of oil that contains 2.5 mg of THC. A total of 50 mg/day of THC and 34 mg/day of CBD can be administered for 4–5 days from one 10-ml glass spray bottle. CogniCann can be stored at room temperature (below 25 °C) for a total of 4 weeks. A certificate of analysis will be provided for each batch upon delivery.\n\nThe placebo will be administered in the same 10-ml glass spray bottle and collected following the procedures describe above. The placebo will comprise a terpene-based oil that contains esters that mimic the smell and taste of CBM.\n\nThe bottles of medication will be provided to the residential aged-care facilities by the affiliated pharmacist. The bottles will be delivered every week and collected again after 7 days of use (even if they are half-full) and returned to the pharmacy, where staff can determine how much was used (or left) and then dispose of the bottles to meet Therapeutic Goods Administration (TGA) requirements. At the start of the titration phase, one bottle will be administered for each participant (because the lower dose of 2.5 mg of THC allows for each bottle to hold 2–3 weeks of the medication). As participants begin to reach a higher dose (titration phase; see Table 1), two bottles will be provided on a weekly basis so that each participant will have sufficient medication to last for 7 days.\n\nData collection\nThe aged-care staff, resident participants with dementia, and nominated next of kin will complete a total of four outcome measures on seven occasions throughout the study. The questionnaires take approximately 20 min to complete and will be completed three times during the first treatment arm (baseline [day 0], after maximum tolerated dose has been reached [day 24], and the end of the treatment cycle [day 42]), three times during the second treatment arm (baseline [day 56], after maximum tolerated dose has been reached [day 80], and the end of the treatment cycle [day 97]) and once following the 2-week washout period after the second treatment arm (day 112). The questionnaires will be administered by the primary researcher.\n\nAdverse events and safety protocol\nAn adverse events protocol will be put into place to minimise any potential harm or risks of receiving additional medication [14]. This will include participants reporting if they have experienced any adverse events 1 h after the increased dose has been administered (see Appendix). If moderate to severe adverse events are recorded (determined as ‘Somewhat worse’ (moderate) or ‘Much worse’ (severe) on the participant’s adverse event record) and these events have not ameliorated by the time for the next dose, the participant will receive the previous best tolerated dose. If the effects of the adverse event(s) have disappeared or become milder and do not interfere with the participant’s daily functioning or well-being, the registered nurse may increase the dose at the indicated rate. Recurrence of adverse events after two attempts to increase the dose will result in the participants remaining at their previous best tolerated dose for the remainder of the intervention period. A participant who experiences an adverse event will stay on the previous dose for another 2 days before the next dose is increased. At the beginning of the titration phase, a staff member at the aged-care facility will be vigilant in monitoring any acute adverse events such as dizziness, discoordination with a danger of falls and injury, and extreme fatigue. Any adverse events recorded will be reported to a facility line manager and will then be communicated to staff during shift changes.\n\nAdditional safety monitoring will be completed by a research nurse who will meet with each participant to discuss their adverse event records and measure their heart rate and blood pressure twice per week. In addition, the participant’s weight and non-invasive body composition measures such as lean body mass, bone mass, body fat percentage, and fat mass will be measured once per week using a portable scale. In addition, a nurse-led review will be completed 2 days into the washout periods to monitor the participant’s withdrawal symptoms once no more medication is being administered.\n\nMeasures\nThe Neuropsychiatric Inventory Questionnaire–Nursing Homes (NPI-NH) [46] is a questionnaire that measures 12 neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability, aberrant motor behaviour, night-time disturbances and appetite changes). The frequency and severity of each symptom is rated (4-point and 3-point Likert scales). A total score can be calculated by adding the first 10 domains together, and all 12 domain scores can be summed in special circumstances where neurovegetative symptoms are of interest, and a carer disruptiveness score (summing the disruptiveness score of the 10 [or 12] behavioural domains) can be calculated. The NPI-NH can be completed in approximately 10 min.\n\nThe Cohen-Mansfield Agitation Inventory (CMAI) is designed to assess agitation cross three domains, namely physically aggressive behaviour, physically non-aggressive behaviour and verbally agitated behaviour [47]. The CMAI comprises 29 items, uses a 7-point Likert scale (never = (1), less than once per week = (2), once or twice per week = (3), several times per week = (4), once or twice per day = (5), several times per day = (6), several times per hour = (7)), and measures four subscales: aggressive behaviour, physically non-aggressive behaviour, verbally agitated behaviour, and hiding and hoarding. A total score of 203 is calculated, with a higher score indicating a higher frequency in behavioural occurrence, and the measure takes approximately 5 min to complete.\n\nThe Quality of Life in Alzheimer’s Disease (QOL-AD) instrument is designed to measure aspects important for an individual’s QOL. The QOL-AD consists of 13 items using a 4-point Likert scale (poor = (1), fair = (2), good = (3), and excellent = (4)) and is designed for both self-report and proxy report [48]. The QOL-AD measures four domains (physical health, mental health, social, and function) and can be completed with people with a wide range of dementia severity [49]. A total score out of 52 is calculated, with a higher score indicating a higher QOL. The self-report version can be completed in about 10–15 min and the proxy report in about 5 min. A composite score can also be calculated (participant QOL-AD × 2 + carer QOL-AD × 3).\n\nThe Abbey Pain Scale comprises six items assessing vocalisation; facial expression; change in body language; and behavioural, physiological and physical changes [50]. This questionnaire uses a 4-point Likert scale (absent = 0, mild = (1), moderate = (2), severe = (3)), and a total score out of 18 is calculated. The severity of pain is indicated as mild (score of 3–7), moderate (8–13) and severe (14+) and can be completed in less than 5 min.\n\nProcess evaluation outcomes\nThe one-page pre- and post-surveys will be administered to aged-care staff and next of kin at the beginning of the first treatment cycle and at the end of the second treatment cycle. These surveys comprise seven to nine questions regarding individuals’ perceptions towards CBM oil use and the symptoms of dementia they find most challenging. A total of six questions will be asked during the focus group discussions. These questions relate to positive and negative observations among those taking CBM oil, as well as changes in perceptions, knowledge and benefits regarding the use of CBM use.\n\nData analysis\nQuantitative\nThe results of questionnaires completed on behalf of the aged-care staff, participants and family members will be analysed using IBM SPSS Statistics version 25 software (IBM, Armonk, NY, USA). The responses from the aged-care staff will be the main responses considered for analysis. Where available, participants and family responses will be included for secondary analysis. To examine group differences, the participants will be categorised according to their treatment cycle group allocation (group A or group B). Descriptive statistics will be derived. Each variable will be tested for normality. For those variables that meet the normality assumption, two-sided paired and/or independent t tests will be used to examine group differences within and between groups. If the normality assumption is violated, then non-parametric tests such as the Wilcoxon signed-rank test will be used. Within-subject differences of the four measurements between the first and second washout periods will be tested using paired t tests to ensure that the washout phase is long enough to rule out any carryover effects [51, 52]. All data collection points will be examined using general linear mixed modelling techniques to see if any changes in behaviour, QOL or pain have occurred over the duration of both treatment cycles. The covariates of weight, average dose of medication, and baseline measures will be controlled for in each model, and any interactions will be tested and reported. The proportion of adverse events during the CBM and placebo phases will be tested and reported for each individual. NPI-NH is the primary outcome measure for this study. All other measures (CMAI, QOL-AD, and Abbey Pain Scale) have been included for secondary analysis. The CMAI will be analysed using the reliability change methodology compared with the NPI-NH to allow small changes to be reported [53]. The α-value will be set at 0.05. In the instance where a participant withdraws halfway through a treatment cycle, the information collected prior to withdrawal will be retained in the study because their personal information will have been de-identified. The data management of the information collected will follow standard university procedures, be stored in a locked cabinet for a period of 15 years, be stored on a password-protected computer, and be backed up regularly in a secure format.\n\nQualitative\nNVivo 12 software (QSR International, Doncaster, Australia) will be used for qualitative data management and assistance in the analysis of both the pre- and post-surveys and in the focus groups. Qualitative content analysis will be used to analyse the surveys to assess similarities and differences between responses. The focus group results will be transcribed verbatim, and the transcripts will be thematically analysed by repeated readings and a subsequent open coding process followed by line-by-line coding to identify key themes. To avoid bias, a triangulated approach including reflectivity by the primary researcher during the interview process, member checking to establish confirmability, and verbatim quotes to establish credibility will be used. The primary researcher and the research team at the University of Notre Dame Australia will have access only to the final data set. The data will be stored in university computers on a locked storage drive.\n\nDiscussion\nTo our knowledge, this is one of the first trials within Australia to evaluate the use of a purified CBM oil at the individual level among those with dementia to examine behavioural effects, QOL, and pain and discomfort. Only a handful of crossover trials have been conducted [14, 16, 41, 42, 54], although the majority have used fixed doses and have not incorporated an individually tailored dosing regimen. Soto et al. [28] reviewed 18 randomised clinical trials examining drugs prescribed for agitation and aggression and found large variations not only in the chosen questionnaires to measure these symptoms but also in the inclusion criteria. On the basis of their results, Soto et al. [28] suggested that trials lasting 9–12 weeks were adequate for assessing an acute response, whereas longer trials (6–12 months) were effective for assessing the stability of a response. The 18-week duration of this study is appropriate to assess the initial dose response [28], and the trial design is also reflective of other protocols of crossover studies and includes two 2-week washout periods to ensure patient safety and a chance for the medication to metabolise out of the body. For example, Babalonis et al. [31] designed a protocol to examine the use of a THC:CBD oromucosal spray among post-stroke spasticity patients and included two 4-week treatment cycles with a 2-week washout period between both cycles.\n\nThere are a number of strengths of our study. First, all participants will have a medical diagnosis of dementia. This ensures that the diagnosis is in line with the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [55]. Second, the residential aged-care staff spend a large amount of time with the participants, so they will be able to observe small changes, leading to accuracy in recording of the results. When possible, these results will also be compared with information from the participants and their next of kin to examine similarities and differences. Beattie et al. [56] published a protocol paper outlining a national project to collect multiple QOL perspectives from the care staff, family members and those living with dementia. Comparisons between care staff, family members and self-report QOL scores showed a linear relationship between reporters, with the residents often rating their QOL higher than the care staff [57, 58].\n\nAs an additional precautionary step, two separate questionnaires assessing behavioural symptoms have been included to ensure that the smallest effects of CBM oil are observed. A strict safety protocol monitoring of adverse events and nurse-led reviews during the washout periods will also be followed to ensure participant safety, which has been included due to the average age of the participants, additional medications currently prescribed, and the likelihood of having a comorbid condition. Weier and Hall [15] suggested that the therapeutic benefits of CBM are observed among patients with dementia when administered alongside adjacent therapy or medication. In addition, the dose of medication will be titrated to ensure that each participant receives their best tolerated dose and minimises the onset of any adverse events. This process of ‘start low and go slow’ is reflective of other studies as well as government documentation from Queensland Health [59, 60]. Educational training with the aged-care staff will be completed before the first participant is recruited to prevent unexpected issues arising during the trial and to ensure that they are familiar with the structure of the overall research protocol as well as the questionnaires.\n\nThis study has used a holistic approach to gain more in-depth information about BPSD and to capture staff and family members’ perceptions of CBM. The inclusion of the qualitative phase is important because little research has been completed to gain understanding of personal views of CBM use and the effects thereof in this setting. This approach allows the researchers to understand the perceived strengths and challenges in the use of cannabis within an institutional setting. Many symptoms associated with dementia, such as wandering, agitation, aggression, and psychotic behaviours, contribute to fatigue and burnout experienced by many caregivers [61]. Feast et al. [62] reviewed the relationship of BPSD and well-being of informal caregivers (child-adult or spousal caregivers) and found that the most distressing symptoms for caregivers were depressive behaviours, agitation and aggression, apathy (including irritability), aberrant motor behaviours, and delusions.\n\nA number of challenges have been identified in the proposed study. It may be difficult to find those with a dementia diagnosis who have the cognitive capacity to give informed consent, because many experience a loss of short-term memory, intellectual reasoning, rationality, and social skills [1, 2]. This may lead to difficulty in recruiting participants into the trial and excluding those who do not have the capacity to give informed consent; yet, they are potentially the ones who exhibit a greater number of behavioural occurrences. Those who experience mild to moderate dementia still exhibit symptoms such as depression and anxiety and both verbal and physical agitation [2]. However, due to the limited legislation regarding including those who do not have the cognitive capacity to give informed consent in research projects, this limits who can be included in this study. The replication of this study design to include those with a moderate to severe diagnosis would warrant further generalisability of the results. Irreversible progression of cognitive impairment, the associated complications and comorbidities, and frailty of the participants may lead to participants dropping out of the study. To accommodate this, we have included a 20% increase in the sample size. It is also difficult to know if the questionnaires chosen for this study are suitable and sensitive enough to measure the changes attributed to the use of CBM oil, because no ‘gold standard’ exists to measure BPSD. Therefore, both the NPI-NH and the CMAI have been selected to account for the small effects. The pharmacodynamics of the medication will be monitored during the treatment cycles through the use of non-invasive body composition measures and monitoring of heart rate, blood pressure and weight. These measures will be collected by a research nurse external to the aged-care facilities to improve the feasibility of the study, to avoid additional workloads placed on the aged-care staff, and to ensure that each participant is receiving their best tolerated dose. In addition, only one residential staff member has been selected to complete the questionnaires, because they spend a great deal of time with the residents and can report symptoms easily. Independent reviews have not been selected for this study, because they are unfamiliar to the participants, which may lead to inaccuracy in recording of the results.\n\nTrial status\nThe trial has been registered with the Australian New Zealand Clinical Trials Registry. The registration number is ACTRN12619000474156, and the trial was registered on 21 March 2019. Recruitment is set to begin in Feburary 2020. The approximate date that the recruitment will be completed is 20 July 2020.\n\nSupplementary information\n\nAdditional file 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist.\n\n \n\n\nAppendix\nAdverse events associated with THC and CBD\nAdverse events will most likely occur within 1 h of administration of the medication but will often resolve within 48 h of treatment. Participants will report their adverse events to make sure the titration is appropriate for them.\n\nCompared with how you normally feel, have you experienced a change in any of the symptoms described below in the last hour? Tick the most appropriate box below.\n\tNo\tYes (tick box below)\t\nBetter\tSomewhat better\tSame as usual\tSomewhat worse\tMuch worse\t\nDrowsiness/fatigue\t\t\t\t\t\t\t\nDizziness\t\t\t\t\t\t\t\nDry mouth\t\t\t\t\t\t\t\nSore throat\t\t\t\t\t\t\t\nAnxiety\t\t\t\t\t\t\t\nNausea\t\t\t\t\t\t\t\nMemory decline or attention deficits\t\t\t\t\t\t\t\nJoy or euphoria\t\t\t\t\t\t\t\nBlurred vision\t\t\t\t\t\t\t\nHeadache\t\t\t\t\t\t\t\nParanoia\t\t\t\t\t\t\t\nDepression\t\t\t\t\t\t\t\nLack of coordination\t\t\t\t\t\t\t\nDiarrhoea\t\t\t\t\t\t\t\nAppetite\t\t\t\t\t\t\t\nSleep disturbance\t\t\t\t\t\t\t\nTo be completed during the titration phase and following the last dose in each treatment arm\n\n\n\nAbbreviations\nBPSDBehavioural and neuropsychiatric symptoms of dementia\n\nCBDCannabidiol\n\nCBMCannabinoid-based medicine\n\nCMAICohen-Mansfield Agitation Inventory\n\nMMSEMini Mental State Examination\n\nNPI-NHNeuropsychiatric Inventory Questionnaire–Nursing Homes\n\nQOLQuality of life\n\nQOL-ADQuality of Life in Alzheimer’s disease\n\nTGATherapeutic Goods Administration\n\nTHCDelta-9-tetrahydrocannabinol\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s13063-020-4085-x.\n\nAcknowledgements\nThis research is financially support by MGC Pharmaceuticals Ltd., an Australian registered company with global connections that specialises in the manufacture of CBM in its good manufacturing practice (GMP)-certified laboratory.\n\nAuthors’ contributions\nAT, CB, MB and JC designed the trial protocol alongside MGC Pharmaceuticals Ltd. AT drafted the manuscript, and CB, MC, AV, JS and JC contributed to the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis project has been fully funded by MGC Pharmaceuticals. MGC Pharmaceuticals informed the design of the study. They will not be involved in the data collection or in the analysis or interpretation of the data. Meetings held between UNDA and MGC Pharmaceuticals during the collection and analysis of data will only be outlined in a general sense. No specific information about the results will be shared.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nEthics approval has been granted by the Human Research Ethics Committee at the University of Notre Dame Australia (UNDA; approval number 018091F). All participants, including the residents and their family members, will need to consent to participate. The results gathered beyond this protocol paper will be presented for the total sample, not for individual cases, and all participants will be given a unique identification number to de-identify their information.\n\nCompeting interests\nThe authors declare that there may be a perceived conflict of interest in undertaking research funded by MGC Pharmaceuticals, the manufacturer of the drug used in the trial; a number of precautionary steps have been implemented to minimise these. These steps include input on study design and drug doses obtained in the development of the research protocol and securing TGA approval for provision of the drug. All MGC Pharmaceuticals staff will be excluded from the trial itself, including the data collection as well as analysis and interpretation of the data. In joint management meetings, the progress of the study will only be discussed in broad terms to ensure compliance with budgetary issues and appropriate responses to any serious adverse events. UNDA has written permission from MGC Pharmaceuticals Ltd. for a worldwide, non-exclusive, royalty-free license to use the project intellectual property for non-commercial research purposes, including consent to publish research findings regardless of the results. The results will be disseminated via brief reports provided to the participating aged care facilities, as well as through manuscript publications and conference presentations.\n==== Refs\nReferences\n1. Alzheimer’s Disease International. The global voice on dementia 2017. https://www.alz.co.uk/. Accessed 5 Jan 2018.\n2. Anand A Khurana P Chawla J Sharma N Khurana N Emerging treatments for the behavioral and psychological symptoms of dementia CNS Spectr 2018 23 6 361 369 10.1017/S1092852917000530 28911339 \n3. Kales HC Gitlin LN Lyketsos CG Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. 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Ettema TP Dröes RM de Lange J Mellenbergh GJ Ribbe MW A review of quality of life instruments used in dementia Qual Life Res 2005 14 3 675 686 10.1007/s11136-004-1258-0 16022061 \n58. Gräske J Verbeek H Gellert P Fischer T Kuhlmey A Wolf-Ostermann K How to measure quality of life in shared-housing arrangements? A comparison of dementia-specific instruments Qual Life Res 2014 23 2 549 559 10.1007/s11136-013-0504-8 23975378 \n59. Lichtman AH Lux EA McQuade R Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain J Pain Symptom Manag 2018 55 2 179 88.e1 10.1016/j.jpainsymman.2017.09.001 \n60. Queensland Health Clinical guidance: for the use of medicinal cannabis products in Queensland 2018 \n61. Reese TR Thiel DJ Cocker KE Behavioral disorders in dementia: appropriate nondrug interventions and antipsychotic use Am Fam Physician 2016 94 4 276 282 27548592 \n62. Feast A Moniz-Cook E Stoner C Charlesworth G Orrell M A systematic review of the relationship between behavioral and psychological symptoms (BPSD) and caregiver well-being Int Psychogeriatr 2016 28 11 1761 1774 10.1017/S1041610216000922 27345942\n\n", "fulltext_license": "CC BY", "issn_linking": "1745-6215", "issue": "21(1)", "journal": "Trials", "keywords": "Behavioural and neuropsychiatric symptoms of dementia (BPSD); Crossover trial; Dementia; Medicinal cannabis; Pain; Quality of life", "medline_ta": "Trials", "mesh_terms": "D000368:Aged; D002186:Cannabinoids; D018592:Cross-Over Studies; D003704:Dementia; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D064086:Medical Marijuana; D000073216:Mental Status and Dementia Tests; D009735:Nursing Homes; D010146:Pain; D010147:Pain Measurement; D010938:Plant Oils; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome", "nlm_unique_id": "101263253", "other_id": null, "pages": "188", "pmc": null, "pmid": "32059690", "pubdate": "2020-02-14", "publication_types": "D000078325:Clinical Trial Protocol; D016428:Journal Article", "references": "25230245;28923526;27624148;25678176;14966439;26482028;19370677;27561138;27267317;1202204;24634659;28088032;27665036;28911339;28861514;28833749;21364345;12021425;25752889;15258006;28940504;16521031;31559336;17140265;30383388;28300462;25972490;16239180;14583744;27345942;16230747;25899853;9309469;28457054;24635665;28631194;25821504;25024327;27548592;28636769;27713372;21954480;26046666;9153155;26757043;28112021;16022061;23975378;25226218;22305029;25801347;22567063;18081000;25237116;23597932", "title": "Use of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial.", "title_normalized": "use of cannabinoid based medicine among older residential care recipients diagnosed with dementia study protocol for a double blind randomised crossover trial" }

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{ "abstract": "Renal tubular acidosis (RTA) is a rare complication of renal involvement of systemic lupus erythematosus (SLE). We describe a 24-year-old male with type IV lupus nephropathy as a presenting manifestation of SLE. He presented with improvement of renal function following induction therapy with three pulses of methylprednisolone and 500 mg biweekly pulses of cyclophosphamide. However, a week after the first pulse of cyclophosphamide, the patient presented with a significant increase in legs edema and severe hyperkalemia. Type IV RTA associated with hyporeninemic hypoaldosteronism was suspected in the presence of metabolic acidosis with a normal anion gap, severe hyperkalemia without worsening renal function, and urinary pH of 5. RTA was confirmed with a transtubular potassium concentration gradient of 2 and low levels of plasma aldosterone, renin, angiotensin II, and cortisol. Intravenous bicarbonate, high-dose furosemide, and fludrocortisone were administered with normalization of potassium levels and renal function.", "affiliations": "Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.;Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain [email protected].", "authors": "Sánchez-Marcos|C|C|;Hoffman|V|V|;Prieto-González|S|S|;Hernández-Rodríguez|J|J|;Espinosa|G|G|", "chemical_list": "D000893:Anti-Inflammatory Agents; D001639:Bicarbonates; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D049994:Sodium Potassium Chloride Symporter Inhibitors", "country": "England", "delete": false, "doi": "10.1177/0961203315603143", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "25(3)", "journal": "Lupus", "keywords": "Lupus nephritis; hyperkalemia; renal tubular acidosis", "medline_ta": "Lupus", "mesh_terms": "D000138:Acidosis; D000893:Anti-Inflammatory Agents; D001639:Bicarbonates; D004359:Drug Therapy, Combination; D004487:Edema; D005938:Glucocorticoids; D006801:Humans; D006947:Hyperkalemia; D006994:Hypoaldosteronism; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D020551:Pulse Therapy, Drug; D049994:Sodium Potassium Chloride Symporter Inhibitors; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "9204265", "other_id": null, "pages": "307-9", "pmc": null, "pmid": "26345674", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Renal tubular acidosis type IV as a complication of lupus nephritis.", "title_normalized": "renal tubular acidosis type iv as a complication of lupus nephritis" }

[ { "companynumb": "ES-MYLANLABS-2016M1014296", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075480", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal tubular acidosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Unmasking of previously unidentified disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SANCHEZ-MARCOS C, HOFFMAN V, PRIETO-GONZALEZ S, HERNANDEZ-RODRIGUEZ J, ESPINOSA G. RENAL TUBULAR ACIDOSIS TYPE IV AS A COMPLICATION OF LUPUS NEPHRITIS. LUPUS 2016;25(3):307-309.", "literaturereference_normalized": "renal tubular acidosis type iv as a complication of lupus nephritis", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20160408", "receivedate": "20160408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12249128, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]

{ "abstract": "The authors examined whether lamotrigine is a clinically effective and cost-effective treatment for people with borderline personality disorder.\n\n\n\nThis was a multicenter, double-blind, placebo-controlled randomized trial. Between July 2013 and November 2016, the authors recruited 276 people age 18 or over who met diagnostic criteria for borderline personality disorder. Individuals with coexisting bipolar affective disorder or psychosis, those already taking a mood stabilizer, and women at risk of pregnancy were excluded. A web-based randomization service was used to allocate participants randomly in a 1:1 ratio to receive either an inert placebo or up to 400 mg/day of lamotrigine. The primary outcome measure was score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. Secondary outcome measures included depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, and adverse events.\n\n\n\nA total of 195 (70.6%) participants were followed up at 52 weeks, at which point 49 (36%) of those in the lamotrigine group and 58 (42%) of those in the placebo group were taking study medication. The mean ZAN-BPD score was 11.3 (SD=6.6) among those in the lamotrigine group and 11.5 (SD=7.7) among those in the placebo group (adjusted difference in means=0.1, 95% CI=-1.8, 2.0). There was no evidence of any differences in secondary outcomes. Costs of direct care were similar in the two groups.\n\n\n\nThe results suggest that treating people with borderline personality disorder with lamotrigine is not a clinically effective or cost-effective use of resources.", "affiliations": "From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.;From the Centre for Psychiatry, Imperial College London, Hammersmith Campus, London; the Centre for the Economics of Mental and Physical Health, King's College London; Tees, Esk and Wear Valley NHS Trust, Middlesbrough, U.K.; West London NHS Mental Health Trust, Southall; Oxleas NHS Foundation Trust, Dartford, U.K.; the Division of Psychiatry and Applied Psychology and the Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, U.K.; the Central and North West London NHS Foundation Trust, London; and the Derbyshire Healthcare NHS Foundation Trust, Derby, U.K.", "authors": "Crawford|Mike J|MJ|;Sanatinia|Rahil|R|;Barrett|Barbara|B|;Cunningham|Gillian|G|;Dale|Oliver|O|;Ganguli|Poushali|P|;Lawrence-Smith|Geoff|G|;Leeson|Verity|V|;Lemonsky|Fenella|F|;Lykomitrou|Georgia|G|;Montgomery|Alan A|AA|;Morriss|Richard|R|;Munjiza|Jasna|J|;Paton|Carol|C|;Skorodzien|Iwona|I|;Singh|Vineet|V|;Tan|Wei|W|;Tyrer|Peter|P|;Reilly|Joseph G|JG|;|||", "chemical_list": "D014150:Antipsychotic Agents; D000077213:Lamotrigine", "country": "United States", "delete": false, "doi": "10.1176/appi.ajp.2018.17091006", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-953X", "issue": "175(8)", "journal": "The American journal of psychiatry", "keywords": "Borderline Personality Disorder; Lamotrigine; Mood Stabilizer; Randomized Controlled Trial", "medline_ta": "Am J Psychiatry", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001883:Borderline Personality Disorder; D003362:Cost-Benefit Analysis; D004311:Double-Blind Method; D005260:Female; D017048:Health Care Costs; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D055118:Medication Adherence; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome", "nlm_unique_id": "0370512", "other_id": null, "pages": "756-764", "pmc": null, "pmid": "29621901", "pubdate": "2018-08-01", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial.", "title_normalized": "the clinical effectiveness and cost effectiveness of lamotrigine in borderline personality disorder a randomized placebo controlled trial" }

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THE CLINICAL EFFECTIVENESS AND COST?EFFECTIVENESS OF LAMOTRIGINE IN BORDERLINE PERSONALITY DISORDER: A RANDOMIZED PLACEBO?CONTROLLED TRIAL. 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{ "abstract": "Omeprazole significantly increases duodenal prostaglandin E2 synthesis. Prostaglandins are involved in hair growth regulation: prostaglandin E2 and prostaglandin F2 alpha stimulate hair growth, and prostaglandin D2 has an inhibitory effect. The use of omeprazole can cause acquired generalized hypertrichosis by increasing prostaglandin E2 levels.", "affiliations": "Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Dermatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.;Department of Pediatrics, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.", "authors": "Elosua-González|Marta|M|http://orcid.org/0000-0002-4227-9316;Campos-Domínguez|Minia|M|http://orcid.org/0000-0002-4638-2265;Bancalari|Daniel|D|;Noguera-Morel|Lucero|L|;Hernández-Martín|Angela|A|;Huerta-Aragonés|Jorge|J|;Torrelo|Antonio|A|http://orcid.org/0000-0002-5940-6916", "chemical_list": "D054328:Proton Pump Inhibitors; D009853:Omeprazole", "country": "United States", "delete": false, "doi": "10.1111/pde.13496", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "35(4)", "journal": "Pediatric dermatology", "keywords": "drug reaction; hair disorders", "medline_ta": "Pediatr Dermatol", "mesh_terms": "D002648:Child; D006801:Humans; D006983:Hypertrichosis; D007223:Infant; D008297:Male; D009853:Omeprazole; D054328:Proton Pump Inhibitors", "nlm_unique_id": "8406799", "other_id": null, "pages": "e212-e214", "pmc": null, "pmid": "29582462", "pubdate": "2018-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Omeprazole-induced hypertrichosis in two children.", "title_normalized": "omeprazole induced hypertrichosis in two children" }

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{ "abstract": "Baclofen is used in the treatment of muscle spasms by acting as an agonist GABAB receptors. Limited case reports describing baclofen withdrawal-induced delirium have largely been demonstrated to occur upon cessation of intrathecal baclofen administration. Fewer reports have characterized the presentation from oral baclofen withdrawal. We describe a case of a patient, MM, who presented with hyperactive delirium with various, associated, behavioral, perceptual, cognitive, and movement disturbances following abrupt withdrawal of oral baclofen. Symptomatic management of occurring during the withdrawal state with antipsychotics and benzodiazepines has been reported previously. Similarly, MM's perceptual and behavioral disturbances were managed with antipsychotics during her admission. However, addressing the underlying cause by reinstating and slowly tapering off baclofen has also been demonstrated to be an effective, targeted approach.", "affiliations": "Psychiatry, University of Kentucky, Bowling Green, USA.;Psychiatry, University of Kentucky, Bowling Green, USA.", "authors": "Sanders|Benjamin J|BJ|;Ali|Ziad|Z|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.14979", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14979\nPsychiatry\nOral Baclofen Withdrawal Resulting in Hyperactive Delirium: A Case Report\nMuacevic Alexander\nAdler John R\nSanders Benjamin J 1\nAli Ziad 1\n1 Psychiatry, University of Kentucky, Bowling Green, USA\nBenjamin J. Sanders [email protected]\n12 5 2021\n5 2021\n13 5 e1497912 5 2021\nCopyright © 2021, Sanders et al.\n2021\nSanders et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/59197-oral-baclofen-withdrawal-resulting-in-hyperactive-delirium-a-case-report\nBaclofen is used in the treatment of muscle spasms by acting as an agonist GABAB receptors. Limited case reports describing baclofen withdrawal-induced delirium have largely been demonstrated to occur upon cessation of intrathecal baclofen administration. Fewer reports have characterized the presentation from oral baclofen withdrawal. We describe a case of a patient, MM, who presented with hyperactive delirium with various, associated, behavioral, perceptual, cognitive, and movement disturbances following abrupt withdrawal of oral baclofen. Symptomatic management of occurring during the withdrawal state with antipsychotics and benzodiazepines has been reported previously. Similarly, MM’s perceptual and behavioral disturbances were managed with antipsychotics during her admission. However, addressing the underlying cause by reinstating and slowly tapering off baclofen has also been demonstrated to be an effective, targeted approach.\n\noral\nbaclofen\ndelirium\npsychosis\nwithdrawal\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nBaclofen is a synthetic chlorophenyl-butanoic acid derivative that is utilized for treatment of muscle spasms by acting as an agonist on GABAB receptors [1]. Abrupt withdrawal of baclofen has been found to demonstrate a range of adverse reactions including behavioral, perceptual, emotional, and movement disturbances [2-5]. We present a case demonstrating the evolving presentation of oral baclofen withdrawal to improve early recognition and expedition of appropriate management.\n\nCase presentation\n\nMM is a 58-year-old female who presented to the emergency department (ED) on four separate occasions, all days apart from each other, with complaints of twitching in her upper and lower extremities, lower extremity weakness, and falls that had become increasingly worse over the past four days.\n\nMM had a past psychiatric history significant for depression and past medical history significant for fibromyalgia and chronic back pain, which was managed with trazodone 100 mg nightly, baclofen 10 mg three times daily, as needed, oxycodone 10 mg every 8 hours, as needed, and zolpidem 10 mg nightly.\n\nDuring her initial evaluation in the emergency room, MM demonstrated significant difficulty with concentration, tangential and disorganized thinking with occasional non-goal directed responses, impaired reasoning, “strange affect,” “bizarre behaviors,” with one provider reporting she was “talking out of her head.” Upon evaluation, a basic metabolic panel (BMP) found to be significant for an acute kidney injury with a blood urea nitrogen (BUN) of 36 and creatinine of 1.09 and mildly tachycardic and tachypneic. All other initial laboratory results, including complete blood count (CBC) and urinalysis, were found to be unremarkable. Urine drug screen was positive for oxycodone, to which she was prescribed. While in the ED, psychiatry was consulted for evaluation for disposition.\n\nUpon evaluation, MM endorsed significant paranoia towards the nursing staff in the ED. She also demonstrated tangential thought processes with flight-of-ideas. She reported experiencing auditory hallucinations in the form of laughter and was observed responding to internal stimuli. She was found to have intact short- and long-term memory; however, she was alert and oriented only to self and location. She is also observed to have bilateral lower extremity weakness and abnormal upper extremity movements. She reported her mood as depressed, but demonstrated an expansive and incongruent affect.\n\nCollateral information was obtained from MM’s son, who stated that he had also first noticed MM’s twitching roughly four days prior to her first ED visit. He also reported that around that same time, she had been intermittently appearing disoriented, demonstrating disorganized speech, and believed that MM had been experiencing auditory hallucinations. He reported that at her baseline, MM was coherent and oriented, and has never been observed responding to internal stimuli in the past.\n\nAt that time, it was recommended that MM be admitted to the hospital and worked up for medical/neurological causes for delirium. Initially, she was not continued on any of her home medications. On her first night after admission, MM required one PRN of 5 mg oral olanzapine and another 10 mg PRN of intramuscular ziprasidone for agitation. A head CT was ordered for acute mental status change and found only to demonstrate chronic small vessel disease. An EEG was also ordered and demonstrated mild to moderate diffuse encephalopathy. A urine culture found to be positive for E. coli; however, as she was asymptomatic, the primary medical team did not treat her asymptomatic bacturia.\n\nOn day 2 of MM’s hospital stay, she was observed to be alert and oriented to self and location with fluctuating orientation to location. MM continued to demonstrate involuntary twitches in the upper and lower extremities. At times, her speech was incoherent and disorganized. She was also occasionally observed responding to internal stimuli. Her affect was described as bizarre with inappropriate affect and incongruent to the stated mood of being “tired.” It was at this time, additional collateral was able to be obtained from MM’s daughter, who stated that MM had been taking up to triple her prescription of baclofen. Based on the information obtained from her daughter, as well as the previous information from her son and pharmacy records, it was believed that MM had run out of her baclofen about four days prior to her first presentation to the ED. This coincided with the first onset of her symptoms. It was also believed by some members of her care team that MM may have taken all of her prescribed baclofen and had recently run out in the days leading up to her presentation in the ED. For symptomatic management, psychiatry started MM on risperidone 1 mg twice daily for hallucinations and overnight agitation. Based on the information received from collateral, MM continued to be observed for delirium. However, as the treating teams were unsure whether MM’s presentation was due to baclofen overdose or withdrawal, MM continued to only receive symptomatic management early on during her stay.\n\nOver the next two days, MM intermittently continued to be observed responding to internal stimuli and demonstrating bizarre behaviors, thought blocking, intermittent poverty of thought, impaired concentration, and fluctuating orientation. While the involuntary twitching in her extremities continued to decrease in frequency and intensity. Throughout her stay, MM continued to receive intravenous fluids. While her BUN and creatinine peaked on the third day of her admission at 56 and 2.84, respectively, with continued fluids her BUN and creatinine trended downwards with her last BUN and creatinine recorded at 34 and 1.17, respectively.\n\nOn day 6, MM was found to be much more calm and cooperative when seen by the psychiatry team on rounds. She was alert and oriented x3. Her thought processes were much more linear, goal-directed, and coherent. No bizarre behaviors or gestures were observed. While interviewing MM, she did report that she had been over-using her baclofen, but was unable to recall precisely how many pills she was taking daily. After discussion with the treating teams, based on MM’s presentation it was believed that delirium was primarily due to baclofen withdrawal that may have been exacerbated by an acute kidney injury. Psychiatry discussed the potential for future baclofen-induced delirium, especially if not taken as prescribed, with MM. She was discharged home with a plan to follow up with psychiatry and neurology on an outpatient basis.\n\nDiscussion\n\nThe presentation of MM’s symptoms is consistent with previous case reports of baclofen withdrawal. The majority of published case reports of baclofen withdrawal delirium have occurred in the context of intrathecal baclofen administration; fewer case reports have been published examining the presentation of oral baclofen withdrawal delirium [2-6]. MM demonstrated musculoskeletal findings, such as abnormal, involuntary movements in her extremities throughout much of the early course of her hospitalization. Similar, intermittent, involuntary movements, and bilateral pupil dilation have also been described in various case reports regarding individuals presenting with baclofen withdrawal [2-6]. Similar to other accounts, MM demonstrated tachycardia when she presented to the ED; however, MM did not have similar characteristic vital signs, such as hypertension or hyperthermia that have also been reported [5].\n\nAmong MM’s most noteworthy and characteristic symptoms of baclofen withdrawal were her psychiatric symptoms. MM demonstrated significant impairments in her thought processes, which were noted to be tangential, disorganized, non-linear, and with flight of ideas, with one ED physician stating she was “talking out of her head.” Several case reports similarly describe patients in acute baclofen withdrawal who also demonstrated formal thought disorders, with one case report by Arnold et al. (1980) also describing the presentation of a patient in baclofen withdrawal who they described as “talking out of his head” [2-4]. Additionally, MM demonstrated impaired concentration, fluctuating orientation, perceptual disturbances in the form of auditory and visual hallucinations, paranoia, and sleep disturbances consistent with delirium due to baclofen withdrawal.\n\nDue to questions about whether MM’s delirium was due to baclofen withdrawal versus intoxication, MM only received symptomatic management for her perceptual and behavioral disturbances throughout her stay. If this had been identified earlier, MM may have, instead, been restarted on a low-dose baclofen taper, which has been previously documented and recommended as a therapeutic approach [2-6]. In a review of 23 case reports of baclofen withdrawal, Leo and Baer (2005) found that 10 cases (43.5%) were managed by reinstituting baclofen alone, whereas reinstitution of baclofen with another agent, such as an antipsychotic, a benzodiazepine, or an anticonvulsant, were reported in 4 (17.4%), 6 (26.1%), and 1 (4.3%) case(s), respectively [4].\n\nThe presentation of baclofen withdrawal consists of a cluster of signs and symptoms, including perceptual disturbances, sleep disturbance, impaired thought processes, expansive affect, abnormal movements, disorganized speech, impaired attention, and disorientation, which may be variably present. In a patient presenting with these symptoms, it is imperative to rule out medical and pharmacological causes, especially in a patient with no history significant for psychosis or mania. While the majority of published case reports have described patients presenting in delirium from withdrawal from intrathecal baclofen, delirium from oral baclofen withdrawal can also be observed, as was the case with MM. Prompt identification of the etiology of this presentation will help guide subsequent management considerations by providers.\n\nConclusions\n\nLike withdrawal from intrathecal baclofen, withdrawal from oral baclofen can present with various cognitive, behavioral, perceptual, and motor disturbances. While symptomatic management of withdrawal symptoms with antipsychotics and benzodiazepines has been demonstrated, reinstituting and slowly tapering off baclofen has been demonstrated to be more targeted approach and effective approach.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 PubChem Compound Summary for CID 2284, Baclofen 52021 13 2021 2284 2021 https://pubchem.ncbi.nlm.nih.gov/compound/Baclofen\n2 Dyskinesia and psychosis in a patient following baclofen withdrawal Am J Psychiatry Kirubakaran V Mayfield D Rengachary S 692 693 141 1984 6711693\n3 Manic psychosis following rapid withdrawal from baclofen Am J Psychiatry Arnold ES Rudd SM Kirshner H 1466 1467 137 1980 7435695\n4 Delirium associated with baclofen withdrawal: a review of common presentations and management strategies Psychosomatics Leo RJ Baer D 503 507 46 2005 16288128\n5 Intrathecal baclofen overdose and withdrawal Pediatr Emerg Care Shirley KW Kothare S Piatt JH Jr Adirim TA 258 261 22 2006 16651918\n6 Chronic baclofen abuse and withdrawal delirium Aust N Z J Psychiatry Nasti JJ Brakoulias V 86 87 45 2011 21058925\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(5)", "journal": "Cureus", "keywords": "baclofen; delirium; oral; psychosis; withdrawal", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e14979", "pmc": null, "pmid": "34123673", "pubdate": "2021-05-12", "publication_types": "D002363:Case Reports", "references": "6711693;7435695;16651918;16288128;21058925", "title": "Oral Baclofen Withdrawal Resulting in Hyperactive Delirium: A Case Report.", "title_normalized": "oral baclofen withdrawal resulting in hyperactive delirium a case report" }

[ { "companynumb": "US-OXFORD PHARMACEUTICALS, LLC-2113360", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLPIDEM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "077088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACLOFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYCODONE." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Delirium", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Withdrawal syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SANDERS BJ, ALI Z. ORAL BACLOFEN WITHDRAWAL RESULTING IN HYPERACTIVE DELIRIUM: A CASE REPORT. CUREUS. 2021 MAY 12?13(5):E14979.", "literaturereference_normalized": "oral baclofen withdrawal resulting in hyperactive delirium a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210701", "receivedate": "20210701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19480901, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Paradoxical response (PR) in patients on anti-tuberculosis drugs and immune reconstitution inflammatory syndrome (IRIS) in patients started on antiretroviral therapy are well known phenomenon. We encountered a case of a paradoxical response in cerebral nocardiosis in a renal transplant recipient. To our knowledge this phenomenon in cerebral nocardiosis has not been reported earlier in literature.", "affiliations": "Consultant Internal Medicine and Infectious Diseases, Mumbai, Maharashtra.;Infectious Diseases Fellow, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.;Consultant Nephrologist, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.;Consultant Microbiology, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.;Consultant Microbiology, PD Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra.", "authors": "Soman|Rajeev|R|;Koparkar|Vidyullata|V|;Almeida|Alan|A|;Shetty|Anjali|A|;Rodrigues|Camilla|C|", "chemical_list": null, "country": "India", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0004-5772", "issue": "66(9)", "journal": "The Journal of the Association of Physicians of India", "keywords": null, "medline_ta": "J Assoc Physicians India", "mesh_terms": "D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D016030:Kidney Transplantation; D009617:Nocardia Infections; D014376:Tuberculosis", "nlm_unique_id": "7505585", "other_id": null, "pages": "91-92", "pmc": null, "pmid": "31321940", "pubdate": "2018-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Paradoxical Response in Cerebral Nocardiosis in a Renal Transplant Recipient.", "title_normalized": "paradoxical response in cerebral nocardiosis in a renal transplant recipient" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TMP?SMX" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin mass", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary nocardiosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sensory disturbance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain abscess", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Monoparesis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20150920" } }, "primarysource": { "literaturereference": "SOMAN R, KOPARKAR V, ALMEIDA A, SHETTY A, RODRIGUES C. PARADOXICAL RESPONSE IN CEREBRAL NOCARDIOSIS IN A RENAL TRANSPLANT RECIPIENT. THE JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA. 2018?66:91?2", "literaturereference_normalized": "paradoxical response in cerebral nocardiosis in a renal transplant recipient", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20180911", "receivedate": "20180911", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15371451, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Severe cutaneous adverse reactions (SCAR) to drugs are a crucial public health issue and the use of systemic corticosteroids in SCAR has been controversial.\nTo analyze clinical features, causative drugs, treatment, outcomes, and prognostic factors of SCAR in the case-series of 173 patients, and add more information to the debate of using systemic corticosteroids in SCAR management.\nA retrospective study of 173 SCAR patients diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) at a tertiary care institution in China between January 2014 and December 2017 was conducted.\nOf 173 patients, allopurinol, carbamazepine, and antibiotics are the most frequently implicated drugs for DRESS (40.4%), SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, there is a strongly negative correlation between early corticosteroids use and the progression (p=0.000) and severity (p=0.01) of skin lesions. However, there is no association between early corticosteroids use and the mortality of SCAR (odds ratio: 1.01, 95% confidence interval: 0.95~1.08). In addition, lymphadenopathy, eosinophilia, and interval from onset to corticosteroids treatment were correlated with SCAR prognosis.\nPrompt short-course systemic corticosteroids use is associated with early-stage skin lesions remission without influencing the disease mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR.", "affiliations": "Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.", "authors": "Xu|Zhongyi|Z|https://orcid.org/0000-0001-8158-0825;Shen|Jie|J|https://orcid.org/0000-0003-2504-4491;Yang|Yiwen|Y|https://orcid.org/0000-0003-0145-7283;Yuan|Ruoyue|R|https://orcid.org/0000-0001-6970-8611;Xiang|Leihong Flora|LF|https://orcid.org/0000-0003-2080-0550;Zhang|Chengfeng|C|https://orcid.org/0000-0002-1302-5667", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.5021/ad.2019.31.5.545", "fulltext": "\n==== Front\nAnn Dermatol\nAnn Dermatol\nAD\nAnnals of Dermatology\n1013-9087\n2005-3894\nThe Korean Dermatological Association; The Korean Society for Investigative Dermatology\n\n10.5021/ad.2019.31.5.545\nOriginal Article\nSevere Cutaneous Adverse Reactions: A Single-Center Retrospective Study of 173 Patients in China\nhttps://orcid.org/0000-0001-8158-0825\nXu Zhongyi *\nhttps://orcid.org/0000-0003-2504-4491\nShen Jie 1*\nhttps://orcid.org/0000-0003-0145-7283\nYang Yiwen\nhttps://orcid.org/0000-0001-6970-8611\nYuan Ruoyue\nhttps://orcid.org/0000-0003-2080-0550\nXiang Leihong Flora\nhttps://orcid.org/0000-0002-1302-5667\nZhang Chengfeng\nDepartment of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.\n1 Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China.\nCorresponding author: Chengfeng Zhang, Department of Dermatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, China. Tel: 86-02152889999, Fax: 86-02152887783, [email protected]\n*These two authors contributed equally to this work.\n\n10 2019\n30 8 2019\n31 5 545554\n30 5 2019\n09 7 2019\n15 7 2019\nCopyright © 2019 The Korean Dermatological Association and The Korean Society for Investigative Dermatology\n2019\nThe Korean Dermatological Association and The Korean Society for Investigative Dermatology\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nSevere cutaneous adverse reactions (SCAR) to drugs are a crucial public health issue and the use of systemic corticosteroids in SCAR has been controversial.\n\nObjective\n\nTo analyze clinical features, causative drugs, treatment, outcomes, and prognostic factors of SCAR in the case-series of 173 patients, and add more information to the debate of using systemic corticosteroids in SCAR management.\n\nMethods\n\nA retrospective study of 173 SCAR patients diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) at a tertiary care institution in China between January 2014 and December 2017 was conducted.\n\nResults\n\nOf 173 patients, allopurinol, carbamazepine, and antibiotics are the most frequently implicated drugs for DRESS (40.4%), SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, there is a strongly negative correlation between early corticosteroids use and the progression (p=0.000) and severity (p=0.01) of skin lesions. However, there is no association between early corticosteroids use and the mortality of SCAR (odds ratio: 1.01, 95% confidence interval: 0.95~1.08). In addition, lymphadenopathy, eosinophilia, and interval from onset to corticosteroids treatment were correlated with SCAR prognosis.\n\nConclusion\n\nPrompt short-course systemic corticosteroids use is associated with early-stage skin lesions remission without influencing the disease mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR.\n\nAcute generalized exanthematous pustulosis\nDrug reaction with eosinophilia and systemic symptoms\nStevens-Johnson syndrome\nSystemic corticosteroids treatment\nToxic epidermal necrolysis\nNational Natural Science Foundation of China https://doi.org/10.13039/501100001809 81573064 81472901 Shanghai Sailing Program 19YF1404800\n==== Body\nINTRODUCTION\n\nSevere cutaneous adverse reactions (SCAR) to drugs are among the most life-threatening conditions involving the skin, mainly encompassing drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP)1. DRESS is a hypersensitivity reaction, characterized by a variable combination of heterogenous clinical presentations2, such as fever, lymphadenopathy, eosinophilia, facial edema, erythroderma and even internal organ involvement3. SJS/TEN is known as a drug-induced hypersensitivity reaction, showing atypical target lesions and bullous lesions with acute exanthema. SJS and TEN are differentiated by the extent of epidermal detachment (SJS with body surface area [BSA] <10%, TEN with BSA >30%, and anything in-between called SJS-TEN overlap syndrome)4. AGEP is characterized by the rapid development of multiple non-follicular, sterile pustules on an erythematous base, mainly attributed to drugs, especially antibiotics, in the majority of cases5.\n\nGiven the severity of SCAR, numerous studies have been conducted. However, to date no specific treatment has been universally accepted. Meanwhile, information of SCAR patients in Asian population was extremely limited. In this retrospective study, we determined the reasons for administration in patients hospitalized with SCAR, the clinical pattern of reactions and the drugs causing adverse reactions in the biggest department of dermatology in China. Most notably, we aimed to examine the role of systemic corticosteroids in SCAR treatment and explore the potential prognostic factors of SCAR.\n\nMATERIALS AND METHODS\n\nPatient selection\n\nA retrospective review of electronic medical records was performed for all patients admitted to Department of Dermatology, Huashan Hospital as DRESS, SJS/TEN, and AGEP between January 2014 and December 2017. Inclusion criteria for this study required that patients met the diagnostic guidelines set by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR)6 for DRESS and SJS/TEN or the modified European Study of Severe Cutaneous Adverse Reactions (EuroSCAR) described by Sidoroff et al.7 for AGEP. No patients were lost to follow-up in this retrospective study. Informed consent was obtained from all patients to use their electronic medical data. The study protocol was approved by the Ethical Committee of Huashan Hospital (IRB no. KY2019-316).\n\nAssessment of drug causality\n\nThe drugs responsible for SCAR were defined as previously described67. The evaluation of drug causality was decided by a group of experienced dermatologists. In brief, if a drug was used continuously for more than three months, withdrawn for more than 14 days, or with a latent period less than three days, it would not be considered as the culprit drug for DRESS or SJS/TEN6. However, latent period for AGEP could be less than three days (typically within 48 hours or 24 hours for antibiotics)8. The “latent period” referred to the period from drug initiation to symptom onset. Moreover, previous use without a drug eruption history decreased suspicion, whereas an earlier reaction prioritized the drug. Hereafter, the remaining suspected drugs were re-evaluated based on the literature review. For cases with several suspected drugs remained, those with high notoriety were firstly considered (listed in Table 1) and those with low notoriety were marked as ‘possible’ (not listed in Table 1). Moreover, the sensitizing properties of different drugs were also taken into account.\n\nAssessment of SCAR outcomes\n\nClinical information with regards to demographic data, comorbidities, latency, and duration from onset to maximum BSA or BSA detachment (maximum BSA detachment for SJS/TEN and maximum BSA skin lesion involvement for DRESS and AGEP), maximum BSA or BSA detachment, time from onset to pharmacotherapy, co-administration of corticosteroids and intravenous immunoglobulin (IVIG) was recorded and analyzed. Outcomes analyzed for pharmacotherapy were progression of disease (defined as duration from the index day to maximum BSA or BSA detachment), severity of disease (maximum BSA or BSA detachment) and mortality. The 25th and 75th percentile of the time length of the lesions withdrawal by 50% were calculated, and prognosis were defined as good when 50% of the lesions withdrew less than seven days.\n\nStatistical analysis\n\nLinear regression analysis was applied to explore the association between the time from onset to corticosteroids treatment and progression of disease (duration from the index day to maximum BSA or BSA detachment) or severity of disease (maximum BSA or BSA detachment), while mortality analysis was based on logistic regression. Linear regression models were adjusted for age, sex, and disease classification (SJS/TEN, DRESS or AGEP) and co-administration of IVIG in order to take into account the confounding factors. In terms of prognostic factor analysis of SCAR, chi-squared test and one-way ANOVA were applied for univariate analysis. Then, the variables significantly associated with prognosis of SCAR in univariate analysis and the variables of great clinical concerns were further included in Cox regression analysis and enter selection was applied. The categorical variables were coded. The threshold for significance was set at p-value <0.05. All statistical analyses were performed using IBM SPSS Statistics ver. 21.0 software (IBM Corp., Armonk, NY, USA).\n\nRESULTS\n\nDemographics\n\nAs shown in Table 2, 173 SCAR patients were studied in this study. SJS/TEN was the most prevalent SCAR observed (55.5%, 96 cases), followed by DRESS (32.9%, 57 cases) and AGEP (11.6%, 20 cases). Males were predominant (1.48:1) in DRESS and females were predominant (0.54:1) in AGEP, whereas the number of males and females were similar for SJS/TEN. The mean period from drug initiation to symptom onset is 27.4 days for DRESS, 14.3 days for SJS/TEN, and 6.2 days for AGEP. The most common underlying diseases justifying the use of drugs were hyperuricemia or gout in DRESS, infection in SJS/TEN and AGEP.\n\nClinical characteristics\n\nThe clinical characteristics of the 173 SCAR patients were summarized in Table 3. Fever ≥38.5℃ was documented in 75% of DRESS patients, 83% of SJS/TEN patients and 50% of AGEP patients. Lymphadenopathy was observed in 63% and 23% of DRESS and SJS/TEN patients respectively. Notably, 19% DRESS patients, 2% SJS/TEN patients and 5% AGEP patients showed peripheral atypical lymphocytes. Leucocytosis was found in 63% of DRESS, 28% of SJS/TEN and 75% of AGEP patients. Leucocytopenia was infrequent, with only 23% in SJS/TEN. Neutrophilia was found in 47% of DRESS, 33% of SJS/TEN and 80% of AGEP patients. Monocytosis was prevalent in DRESS patients (35%) but not in SJS/TEN (16%) and AGEP (25%). Thrombocytosis was infrequent, with only 9% in DRESS and 7% in SJS/TEN patients. Thrombocytopenia was rare, with only 6% in SJS/TEN. Eosinophilia, defined as an absolute eosinophil count ≥700 U/L, was present in 77% of DRESS patients. While in SJS/TEN, only 9% of patients had an absolute eosinophil count ≥700 U/L.\n\nAll patients experienced an acute skin eruption. 91% of DRESS and SJS/TEN patients, and all of the AGEP patients had suggestive rash. The criteria for suggestive rash was facial edema or exfoliative dermatitis in DRESS, edematous erythema, target-like lesions, mucosal involvement, flaccid blisters, and exfoliation in SJS/TEN, and sterile nonfollicular pustules in AGEP6910. The rash was a monomorphic maculopapular in 28% of DRESS patients and only 2% of SJS/TEN patients, while in all other cases it was polymorphous, including variable combinations of other lesions. For example, DRESS patients usually had infiltrated plaques (95%), exfoliation (32%), purpura (26%), eczema-like lesions (19%), and blisters (16%). Whereas, SJS/TEN patients usually had exfoliation (92%), blisters (77%), target-like lesions (43%), and purpura (31%). Facial edema was observed in 86% of DRESS patients, 48% of SJS/TEN patients and 25% of AGEP patients. Mucosal involvement was recorded in 30% of DRESS patients and 94% of SJS/TEN patients. Most popular were oral lesions (21% of DRESS patients and 90% of SJS/TEN patients).\n\nIn terms of systemic involvement, most frequently the reaction affected the liver (95% of DRESS patients, 72% of SJS/TEN patients, and 30% of AGEP patients), followed by kidney (46% of DRESS patients, 55% of SJS/TEN patients, and 5% of AGEP patients) and lung (21% of DRESS patients and 15% of SJS/TEN patients).\n\nCausative drugs\n\nIn this study, two DRESS patients (3.5%), eight SJS/TEN patients (8.3%), and three AGEP patients (15.0%) were not exposed to any medication according to the criteria of culprit drugs in RegiSCAR6 or modified EuroSCAR for AGEP7. As for other SCAR cases, the summary of drug causality was presented in Table 1. In addition, we categorized all SCAR cases by causative drugs into three groups: allopurinol group, carbamazepine group, and other causative drugs group. Univariate analysis of the outcome measures showed difference in the severity of SCAR (p=0.031) but no difference in the progression of SCAR among three causative drugs groups. Further two-two comparisons also showed that the difference between allopurinol group and carbamazepine group (p=0.039) and the difference between carbamazepine group and other causative drugs group were statistically significant (p=0.010). However, when stratified by disease types, causative drugs showed difference only in the severity of SJS/TEN, whereas no differences in the severity of DRESS or AGEP.\n\nTreatment\n\nIn our observational study, 56 DRESS patients (98.2%), 96 SJS/TEN patients (100.0%), and 20 AGEP patients (100.0%) received systemic corticosteroids. Intravenous methylprednisolone was given at 1~1.5 mg/kg/d. Once the progression of the disease was halted, which manifested as no new lesions, Nikolsky sign turning negative, exudation improved, re-epithelialization and laboratory test results being stable, the dose of corticosteroids was tapered promptly. Meanwhile, 43 DRESS patients (75.4%), 88 SJS/TEN patients (91.6%), and four AGEP patients (20.0%) received treatment with IVIG. IVIG was administered at 0.4 g/kg/d for over 5 days. Univariate analysis of the outcome measures showed that early use of systemic corticosteroids was significantly and negatively related to the progression of SCAR (p=0.000) and the severity of SCAR (p=0.001). Further multivariate analysis also indicated the negative linear association of early use of systemic corticosteroids and the progression (p=0.000) and the severity of SCAR (p=0.01) (Table 4). Duration from onset to maximum BSA or BSA detachment will be 0.858-day longer when the initiation of systemic corticosteroids was delayed for 1 day (Table 4). It means later systemic corticosteroids use might prolong the duration of active stage SCAR, and it would take more time for SCAR patients to reach stable stage (no new lesions). Moreover, one-day delay of the systemic corticosteroids use would increase 19.2% of maximum BSA or BSA detachment (Table 4). In contrast, IVIG treatment did not statistically affect the primary outcomes of both the disease progression and severity. Among all 173 SCAR patients, none of them died during their stay in hospital, and only two DRESS patients (3.5%), four SJS/TEN patients (4.2%) and no AGEP patient died in the first three months after discharge. Both two DRESS patients died of lung infection. Three SJS/TEN patients died of multiple organ dysfunction syndrome, and one SJS/TEN patients died of lactic acidosis. For mortality analysis, no statistical difference was revealed between early and delayed systemic corticosteroids use (odds ratio [OR]: 1.01, 95% confidence interval [CI]: 0.95~1.08) (Table 5).\n\nPrognostic factors of SCAR\n\nFollowing risk factors were included in the regression model to analyze their associations with SCAR: disease type, age, sex, lymphadenopathy, eosinophilia, mucosal involvement, internal organ involvement, interval from onset to standard treatment with adequate corticosteroids, combination therapy with IVIG, and causative drugs (Table 6). Multivariate analysis showed disease type (p=0.035), lymphadenopathy (p=0.001), eosinophilia (p=0.019) and interval from onset to standard treatment with adequate corticosteroids (p=0.000) were the independent risk factors for the prognosis of SCAR. Patients with lymphadenopathy had longer time for 50% lesions' withdrawal than those with no lymphadenopathy (OR: 2.356, 95% CI: 1.433~3.875). Moreover, when we categorized eosinophilia into three groups: moderate (<700), high (700~1,500) and higher (>1,500), high levels of eosinophilia proved to be a poor prognosis factor of SCAR, with 2-fold higher risks of longer lesions' withdrawal time (high, OR: 2.709, 95% CI: 1.283~5.721; higher, OR: 2.133, 95% CI: 1.059~4.296), compared with moderate eosinophilia level. Furthermore, interval from onset to standard treatment with adequate corticosteroids was proved to be a protective factor for the prognosis of SCAR (OR: 0.963, 95% CI: 0.943~0.983). However, mucosal involvement, internal organ involvement, co-treatment with IVIG and SCAR causative drug types were not independent prognostic factors for SCAR.\n\nDISCUSSION\n\nPrevious studies showed conflicting results about the incidence of SCAR in different genders. In our study, DRESS occurred more common in male than female. It might be due to the fact that 40.4% DRESS cases had underlying hyperuricemia or gout, which is much more prevalent in men as well11. Whereas in SJS/TEN and AGEP, infection (28.1% for SJS/TEN and 45.0% for AGEP) was the most common underlying disease, which was consistent with previous study12.\n\nAccording to our data, internal organ involvement (98%), facial edema (86%), eosinophilia (77%), high fever (75%), leukocytosis (63%), and lymphadenopathy (63%) were characteristic for DRESS. As for SJS/TEN, the main features next to the ubiquitous exanthema were mucosal involvement (94%), internal organ involvement (89%), fever (83%), and neutrophilia (33%). As for AGEP, the main features were pustules (100%), neutrophilia (80%), leukocytosis (75%), and fever (50%). Notably, our findings revealed that 46 SJS/TEN patients (48%) had facial edema, which was quite different from the traditional concept that facial edema was the warning signal for DRESS and rarely occurred in other SCAR6. We considered that diffuse erythema on face in combination with mucosal involvement like conjunctivae or lips13 could manifest as facial edema in severe SJS/TEN cases. Additionally, 17 DRESS patients (30%) had mucosal involvement, which was similar as previous reported3. Nine SJS/TEN patients (9%) had increased peripheral eosinophil counts, which highlighted that eosinophilia could occur in SCAR other than DRESS14. Some studies even reported that eosinophilia was associated with poor SCAR outcomes151617. Higher percentage of lymphadenopathy in DRESS (63%) than other SCAR was similar to previous studies, which would be explained by the potential activation of virus infections, such as Epstein-Barr virus, cytomegalovirus or human herpesvirus 6 in DRESS181920. Six AGEP (30%) had internal organ involvement, which was similar to previous studies that AGEP-specific hepatitis, nephritis or pneumonia were rare but sometimes occurred2122. Thus, systemic investigations were recommended for all SCAR types.\n\nOver the past few decades, important progress has been made in understanding the pathogenesis of SJS/TEN, especially the role of human leukocyte antigen (HLA) alleles2324. Antiepileptic agents (phenobarbital, carbamazepine, phenytoin, and lamotrigine), minocycline, allopurinol, dapsone, and sulfonamides are the most frequently reported causative drugs of DRESS2526. In our study, the most common culprit drug for DRESS was allopurinol. HLA-B *58:01 has been reported to be associated with allopurinol-induced SCAR27. As for carbamazepine, the leading causative drug for SJS/TEN in our study, HLA-B *15:02 was responsible for carbamazepine-induced SJS/TEN28, and HLA-A *31:01 showed a stronger correlation with carbamazepine-induced DRESS29. Antibiotics were the leading cause of AGEP in our findings, which was also in agreement with previous reports30. However, further studies are required with regard to the limited number of AGEP patients in our study. Notably, 5.3% DRESS, 8.3% SJS/TEN, and 30.0% AGEP cases were caused by traditional Chinese medicine (TCM) use. The associated TCMs were radix isatidis, propolis, scolopendra, salvianolate, sophora flavescens, berberine, paraquat, Leonurus artemisia, bezoar, berberine, notoginseng triterpenes, Cordyceps sinensis, and Platycarya strobilacea. Among those listed, only paraguat has been reported to cause TEN31, and propolis has been reported to cause fixed drug eruption32. All other TCMs were newly reported. Considering the popular application of TCM treatment in Asian cultures, connection between TCM and SCAR needs to be further clarified. In our study, there were still a small number of SCAR cases with no culprit drugs, which was in accordance with previous studies that SCAR could attribute to exposures other than medications, such as infection, foods or transplantation33.\n\nSystemic corticosteroids have long been regarded as the mainstay treatment for SCAR. However it is still controversial how much benefit patients would get from this treatment. Some case series have concluded that the use of systemic steroids were beneficial in reducing morbidity and mortality3435, whereas others suggesting minimal or no benefit in terms of outcome363738. Some earlier observational studies even indicated an increased mortality and a higher frequency of complications for TEN patients treated with systemic steroids394041. Here, we reveal that early steroids therapy could alleviate the severity (p=0.01) and progression (p=0.000) of SCAR without influencing the mortality rate. These results suggest that early shortcourse steroids use is helpful in the initial phase management of SCAR at least in a modern well-equipped tertiary care hospital. Since more than 98.2% SCAR cases received systemic steroids, we could not demonstrate the difference of outcomes with and without systemic steroids use. Further studies with different therapy are required to answer this question.\n\nSCARs are associated with significant morbidity, mortality, and socioeconomic costs. Predicting outcomes for each specific SCAR patient at an early stage would be extremely helpful for physicians to formulate appropriate treatment strategy. However, very few clinical researches have focused on the prognostic factors of SCAR1516174243. According to our results, lymphadenopathy and eosinophilia were associated with a poor outcome. The role of eosinophilia in the outcomes of SCAR has been reported before151617, while lymphadenopathy as a poor prognostic factor for SCAR was reported for the first time. This can be explained by the potential activation of virus infections, such as Epstein-Barr virus, cytomegalovirus or human herpesvirus 6181920.\n\nLimitations of the study included the retrospective design and a predominance of Asian population. Since most SCAR patients in our study had received systemic corticosteroids in combination with IVIG, further case-control studies with larger sample size are required for more detailed research. In addition, there have been no universal rules that could determine the causative drug of SCAR with certainty, and the rule used in this study is imperfect as well. Moreover, the long-term follow-up of SCAR patients post-discharge was lacking. However, due to the fact that the ultimate prospective blinded study needed to provide a more definitive answer to the questions about steroid use in SCAR management is extremely difficult to do, our study is of significance in guiding clinical practice. In conclusion, allopurinol, carbamazepine, and antibiotics were the most frequent implicated drugs for DRESS, SJS/TEN, and AGEP respectively. Hyperuricemia or gout was the most frequent cause of administration in DRESS, and infection was that in SJS/TEN and AGEP. Selection and prescription of those drugs should be more cautiously. Additionally, early initiation of steroids might help prevent the progression of skin lesions and decrease the severity of skin lesions or skin detachment, but had no correlation with mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR. For SCAR patients with lymphadenopathy and eosinophilia, physicians may consider taking a more aggressive therapeutic approach.\n\nACKNOWLEDGMENT\n\nThis work was supported by grants from Natural Science Foundation of China (No. 81573064 and 81472901) and Shanghai Sailing Program (No. 19YF1404800).\n\nWe thank Prof. Xiaoqun Luo for her critical reading, and thank Dr. Shengan Chen and Xiaojin Wu for their excellent technical assistance.\n\nTable 1 Causative drugs of SCAR\n\nAssociated drug\tCase (%)\t\nDRESS\t\t\n Allopurinol\t23 (40.4)\t\n Sulfasalazine\t8 (14.0)\t\n Phenobarbital\t4 (7.0)\t\n Carbamazepine\t4 (7.0)\t\n Mexiletine\t3 (5.3)\t\n Antibiotics (antifungals)\t4 (7.0)\t\n Cephalosporin (cefprozil, cefoxitin)\t2\t\n Amoxicillin\t1\t\n Fluconazole\t1\t\n TCM (radix isatidis, propolis, herbs)\t3 (5.3)\t\n Indomethacin\t2 (3.5)\t\n Other drugs*\t4 (7.0)\t\nSJS/TEN\t\t\n Carbamazepine\t25 (26.0)\t\n Antibiotics\t15 (15.6)\t\n Cephalosporin (cefotaxime, cefmetazole, cefotiam, cefprozil, cefepime)\t6\t\n Levofloxacin\t4\t\n Metronidazole\t2\t\n Amoxicillin\t1\t\n Clarithromycin\t1\t\n Erythromycin\t1\t\n Allopurinol\t11 (11.5)\t\n TCM (berberine, bezoar, leonurus artemisia, paraquat, radix isatidis, salvianolate, scolopendra, sophora flavescens)\t8 (8.3)\t\n Methazolamide\t5 (5.2)\t\n Compound paracetamol and amantadine\t4 (4.2)\t\n Edaravone\t2 (2.0)\t\n Phenytoin\t2 (2.0)\t\n Sulfasalazine\t2 (2.0)\t\n Valaciclovir\t2 (2.0)\t\n Valproate\t2 (2.0)\t\n Other drugs†\t10 (10.4)\t\nAGEP\t\t\n Antibiotics\t8 (40.0)\t\n Cephalosporin (cefaclor, cefotiam, cefepime)\t3\t\n Clindamycin\t2\t\n Azithromycin\t1\t\n Levofloxacin\t1\t\n Isepamicin\t1\t\n TCM (notoginseng triterpenes, radix isatidis, Cordyceps sinensis)\t6 (30.0)\t\n NSAIDS\t2 (10.0)\t\n Paracetamol\t1\t\n Meloxicam\t1\t\n Urea C 14\t1 (5.0)\t\nSCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, TCM: traditional chinese medicine, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, NSAIDS: nonsteroidal anti-inflammatory drugs. *Compound paracetamol and amantadine, flunarizine, oxcarbazepine, and phenytoin. †Amlodipine, dabigatran, fentanyl, ossotide, paracetamol, phenobarbital, pyrazinamide, rabeprazole, tetanus antitoxin, and tropicamide.\n\nTable 2 Demographics\n\n\tDRESS (n=57)\tSJS/TEN (n=96)\tAGEP (n=20)\t\nSex ratio (male/female)\t1.48 (34/23)\t1 (48/48)\t0.54 (7/13)\t\nAge (yr)\t50.5 (32.3~66)\t51.5 (31.8~65)\t36 (31.3~55)\t\nLatent period (d)*\t27.4±4.3\t14.3±2.1\t6.2±2.4\t\nUnderlying disease\t\t\t\t\n Hyperuricemia/gout\t23 (40.4)\t11 (11.5)\t-\t\n Infection†\t8 (14.0)\t27 (28.1)\t9 (45.0)\t\n Inflammatory disease‡\t8 (14.0)\t2 (2.1)\t2 (10.0)\t\n Seizure/paralysis/spasm\t7 (12.3)\t15 (15.6)\t-\t\n Pain§\t5 (8.8)\t14 (14.6)\t3 (15.0)\t\n Others\t5 (8.8)\t19 (19.8)\t3 (15.0)\t\nValues are presented as ratio, median (interquartile range), mean±standard deviation, or number (%). DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, -: not applicable. *The period from drug initiation to symptom onset. †DRESS: respiratory infection (5 cases), vaginitis (1 case), nasosinusitis (1 case), gastroenteritis (1 case). SJS/TEN: respiratory infection (8 cases), eye infection (5 cases), vaginitis (3 cases), duodenal ulcer with Helicobacter pylori infection (2 cases), sepsis (2 cases), cervicitis (2 cases), skin infection (2 cases), gastroenteritis (1 case), tuberculosis (1 case). AGEP: respiratory infection (2 cases), cholecystitis (1 case), gastroenteritis (2 cases), otitis (2 cases), nasosinusitis (1 case), urocystitis (1 case). ‡DRESS: ankylosing spondylitis (4 cases), osteoarthritis (1 case), Crohn's disease (1 case), rheumatic arthritis (1 case), ulcerative colitis (1 case). SJS/TEN: ulcerative colitis (2 cases). AGEP: rheumatic arthritis (1 case), periarthritis humeroscapularis (1 case). §DRESS: neuralgia (2 case), headache (1 case), post-surgery pain (1 case), pharyngalgia (1 case). SJS/TEN: postherpetic neuralgia (5 cases), trigeminal neuralgia (3 cases), headache (3 cases), pharyngalgia (1 case), neuralgia (1 case), and post-surgery pain (1 case). AGEP: pharyngalgia (3 cases).\n\nTable 3 Clinical characteristics\n\nCharacteristic\tDRESS (n=57)\tSJS/TEN (n=96)\tAGEP (n=20)\t\nn\t95% CI\tn\t95% CI\tn\t95% CI\t\nFever ≥38.5℃\t43\t75 (63~85)\t80\t83 (75~89)\t10\t50 (30~70)\t\nLymphadenopathy\t36\t63 (50~74)\t22\t23 (16~32)\t2\t10 (3~30)\t\nAtypical lymphocytes\t11\t19 (11~31)\t2\t2 (0~7)\t1\t5 (1~24)\t\nLeucocytosis\t36\t63 (50~74)\t27\t28 (20~38)\t15\t75 (53~89)\t\nLeucocytopenia\t0\t-\t22\t23 (16~32)\t0\t-\t\nNeutrophilia\t27\t47 (35~60)\t32\t33 (25~43)\t16\t80 (58~92)\t\nLymphocytosis\t0\t-\t0\t-\t0\t-\t\nMonocytosis\t20\t35 (24~48)\t15\t16 (10~24)\t5\t25 (11~47)\t\nThrombocytosis\t5\t9 (4~19)\t7\t7 (4~14)\t0\t-\t\nThrombocytopenia\t0\t-\t6\t6 (3~13)\t1\t5 (1~24)\t\nEosinophilia\t44\t77 (65~86)\t9\t9 (5~17)\t1\t5 (1~24)\t\nGrade 1\t11\t19 (11~31)\t7\t7 (4~14)\t1\t5 (1~24)\t\nGrade 2\t33\t58 (45~70)\t2\t2 (0~7)\t0\t-\t\nExtent of rash >50%\t56\t98 (91~100)\t95\t99 (94~100)\t17\t85 (64~95)\t\nSuggestive rash\t52\t91 (81~96)\t87\t91 (83~95)\t20\t100 (84~100)\t\nFacial edema\t49\t86 (75~93)\t46\t48 (38~58)\t5\t25 (11~47)\t\nMonomorphic maculopapular\t16\t28 (18~41)\t2\t2 (0~7)\t0\t-\t\nPolymorphous maculopapular\t40\t70 (57~80)\t94\t98 (93~99)\t20\t100 (84~100)\t\nUrticarial\t0\t-\t0\t-\t1\t5 (1~24)\t\nExfoliative\t18\t32 (21~44)\t88\t92 (84~96)\t1\t5 (1~24)\t\nLichenoid\t1\t2 (0~9)\t0\t-\t0\t-\t\nPustules\t0\t-\t1\t1 (0~6)\t20\t100 (84~100)\t\nPurpura\t15\t26 (17~39)\t30\t31 (23~41)\t4\t20 (8~41)\t\nInfiltrated plaques\t54\t95 (86~98)\t41\t43 (33~53)\t13\t65 (54~82)\t\nBlisters\t9\t16 (9~27)\t74\t77 (68~84)\t3\t15 (5~36)\t\nTarget-like lesions\t4\t7 (3~17)\t41\t43 (33~53)\t4\t20 (8~41)\t\nEczema-like lesions\t11\t19 (11~31)\t3\t3 (1~9)\t3\t15 (5~36)\t\nMucosal involvement\t17\t30 (20~43)\t90\t94 (86~97)\t0\t-\t\nMouth/throat/lips\t12\t21 (12~33)\t87\t90 (83~95)\t0\t-\t\n Eyes\t3\t5 (2~14)\t53\t55 (45~65)\t0\t-\t\n Genitalia\t9\t16 (9~27)\t69\t72 (62~80)\t0\t-\t\n Other\t1\t2 (0~9)\t21\t22 (15~31)\t0\t-\t\nInternal organ involvement*\t56\t98 (91~100)\t85\t89 (81~93)\t6\t30 (15~52)\t\n 1 Organ involved\t16\t28 (18~41)\t36\t38 (28~47)\t5\t25 (11~47)\t\n 2 Organs involved\t30\t53 (40~65)\t31\t32 (24~42)\t1\t5 (1~24)\t\n >2 Organs involved\t10\t18 (10~29)\t18\t19 (12~28)\t0\t-\t\n Liver\t54\t95 (86~98)\t69\t72 (62~80)\t6\t30 (15~52)\t\n Kidney\t26\t46 (33~58)\t53\t55 (45~65)\t1\t5 (1~24)\t\n Lung\t12\t21 (12~33)\t14\t15 (9~23)\t0\t-\t\n Muscle/heart\t9\t16 (9~27)\t18\t19 (12~28)\t1\t5 (1~24)\t\n Spleen\t5\t9 (4~19)\t1\t1 (0~6)\t0\t-\t\n Pancreas\t1\t2 (0~9)\t5\t5 (2~12)\t0\t-\t\n Other\t0\t-\t1\t1 (0~6)\t0\t-\t\nLeucocytosis >10,000 U/L, Leucocytopenia <4,000 U/L, Neutrophilia >7,000 U/L, Lymphocytosis >4,000 U/L, Monocytosis >1,000 U/L, Thrombocytosis >400,000 U/L, Thrombocytopenia <100,000 U/L, Eosinophilia Grade 1: 700~1,499 U/L, Eosinophilia Grade 2: >1,500 U/L. DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, -: stands for not applicable. *Liver: elevation of liver enzymes (twice the normal value), kidney: elevation of creatinine (twice the normal value) or the occurrence of proteinuria or hematuria, lung: inflammation or interstitial change on X-ray or computerized tomography (CT), muscle: elevation of creatine kinase (CK), heart: elevation of CK-muscle/brain or myoglobin, spleen: splenomegaly reported on ultrasound or CT, pancreas: elevation of serum/uric amylase or lipase, or pancreatic edema reported on CT.\n\nTable 4 Linear regression of SCAR progression and severity (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)\n\n\tUnadjusted linear regression\tAdjusted linear regression\t\nStandardized coefficients β\tp-value\tStandardized coefficients β\tp-value\t\nDuration from onset to maximum BSA or BSA detachment\t\t\t\t\t\n Time from onset to corticosteroids treatment\t0.857\t0.000\t0.858\t0.000\t\n Classification\t\t\t\t\t\n AGEP\t0\t\t0\t\t\n DRESS\t0.285\t0.02\t0.022\t0.758\t\n SJS/TEN\t0.158\t0.195\t0.04\t0.599\t\n Age (yr, linear)\t−0.002\t0.952\t0.011\t0.790\t\n Sex\t0.019\t0.802\t−0.069\t0.085\t\n IVIG\t0.166\t0.029\t0.052\t0.274\t\nMaximum BSA or BSA detachment\t\t\t\t\t\n Time from onset to corticosteroids treatment\t0.0244\t0.001\t0.192\t0.010\t\n Classification\t\t\t\t\t\n AGEP\t0\t\t0\t\t\n DRESS\t0.14\t0.232\t0.099\t0.442\t\n SJS/TEN\t−0.212\t0.07\t−0.225\t0.100\t\n Age (yr, linear)\t−0.108\t0.156\t−0.097\t0.180\t\n Sex\t−0.015\t0.846\t−0.055\t0.445\t\n IVIG\t−0.047\t0.542\t0.026\t0.759\t\nMaximum BSA for AGEP and DRESS, and maximum BSA detachment for SJS/TEN. SCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, BSA: body surface area, IVIG: intravenous immunoglobulin.\n\nTable 5 Logistic regression of mortality (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)\n\n\tUnadjusted logistic regression OR (95% CI)\tAdjusted logistic regression OR (95% CI)\t\nDuration from onset to maximum BSA or BSA detachment\t\t\t\n Time from onset to corticosteroids treatment\t1.01 (0.95~1.08)\t1.02 (0.97~1.09)\t\n Classification\t\t\t\n DRESS\t0.77 (0.14~4.36)\t0.77 (0.13~4.72)\t\n SJS/TEN\t1 1\t\t\n Age (yr, linear)\t1.08 (1.02~1.16)\t1.08 (1.01~1.16)\t\n Sex\t1.85 (0.33~10.41)\t1.58 (0.26~9.49)\t\nMaximum BSA for AGEP and DRESS, and maximum BSA detachment for SJS/TEN. DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, OR: odds ratio, CI: confidence interval, BSA: body surface area.\n\nTable 6 Prognostic factors of SCAR (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)\n\nCovariate\tUnivariate\tMultivariate\t\np-value\tB\tExp (B) (95% CI)\tp-value\t\nDisease type\t0.001\t\t\t0.035\t\n SJS/TEN\t\t\t\t\t\n AGEP\t0.001\t0.717\t2.048 (0.674~6.224)\t0.206\t\n DRESS\t0.046\t−0.683\t0.505 (0.228~1.116)\t0.091\t\nSex\t0.21\t0.297\t1.346 (0.919~1.971)\t0.127\t\nAge (yr)\t\t0\t1.000 (0.989~1.011)\t0.975\t\nLymphadenopathy\t0.025\t0.857\t2.356 (1.433~3.875)\t0.001\t\nEosinophilia\t0.021\t\t\t0.019\t\n <700\t\t\t\t\t\n 700~1,500\t0.01\t0.997\t2.709 (1.283~5.721)\t0.009\t\n >1,500\t0.127\t0.757\t2.133 (1.059~4.296)\t0.034\t\nMucosal involvement\t0.001\t0.207\t1.231 (0.635~2.385)\t0.539\t\nInternal organ involvement\t0.187\t\t\t0.405\t\n No organ involved\t\t\t\t\t\n 1 Organ involved\t0.171\t0.491\t1.633 (0.732~3.644)\t0.231\t\n 2 Organs involved\t0.058\t0.154\t1.166 (0.535~2.540)\t0.699\t\n 3 And more organs involved\t0.046\t0.193\t1.213 (0.523~2.812)\t0.653\t\nInterval from onset to corticosteroids treatment\t\t−0.038\t0.963 (0.943~0.983)\t0.000\t\nIVIG\t0\t−0.36\t0.698 (0.401~1.214)\t0.203\t\nCausative drugs\t0.37\t\t\t0.293\t\n Allopurinol\t\t\t\t\t\n Carbamazepine\t0.161\t\t0.706 (0.391~1.274)\t0.248\t\n Others\t0.35\t\t0.677 (0.412~1.113)\t0.124\t\nSCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, IVIG: intravenous immunoglobulin.\n\nCONFLICTS OF INTEREST: The authors have nothing to disclose.\n==== Refs\n1 Roujeau JC Stern RS Severe adverse cutaneous reactions to drugs N Engl J Med 1994 331 1272 1285 7794310\n2 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Semin Cutan Med Surg 1996 15 250 257 9069593\n3 Kardaun SH Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? 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CH Chung-Yee Hui R Chang CJ Ho HC Yang CH Lin YJ Identifying prognostic factors for drug rash with eosinophilia and systemic symptoms (DRESS) Eur J Dermatol 2011 21 930 937 21951554\n43 Bastuji-Garin S Fouchard N Bertocchi M Roujeau JC Revuz J Wolkenstein P SCORTEN: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol 2000 115 149 153 10951229\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1013-9087", "issue": "31(5)", "journal": "Annals of dermatology", "keywords": "Acute generalized exanthematous pustulosis; Drug reaction with eosinophilia and systemic symptoms; Stevens-Johnson syndrome; Systemic corticosteroids treatment; Toxic epidermal necrolysis", "medline_ta": "Ann Dermatol", "mesh_terms": null, "nlm_unique_id": "8916577", "other_id": null, "pages": "545-554", "pmc": null, "pmid": "33911647", "pubdate": "2019-10", "publication_types": "D016428:Journal Article", "references": "22639874;22828258;20713773;28911824;25592341;12164739;17300272;17340021;22002792;20605253;10951229;9069593;21428769;15743917;17854366;26228174;17919775;26481651;20548906;26354880;7145729;28476287;3767483;23855313;23132554;7487252;7794310;28718873;23866879;20542841;13679697;23855377;21800283;7874336;24749495;11168761;27075126;24597466;23602183;26769645;21204807;28867742;21951554", "title": "Severe Cutaneous Adverse Reactions: A Single-Center Retrospective Study of 173 Patients in China.", "title_normalized": "severe cutaneous adverse reactions a single center retrospective study of 173 patients in china" }

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SEVERE CUTANEOUS ADVERSE REACTIONS: A SINGLE-CENTER RETROSPECTIVE STUDY OF 173 PATIENTS IN CHINA. 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{ "abstract": "The nucleus tractus solitarius and paratrigeminal nucleus, which are implicated in the processing of airway-derived sensory information, are found in the dorsal medulla. The mechanism and localization of higher-order processing of urge to cough is poorly understood, and much of the existing anatomical localization is limited to animal studies.\n\n\n\nA 44-year-old Caucasian lady underwent elective foramen magnum decompression for symptomatic Chiari I malformation; postoperatively she had resolution of Chiari symptoms but developed an intractable neurogenic cough. She has no significant medical history or premorbid respiratory issues. Postoperative magnetic resonance imaging of her head demonstrated signal change in the left dorsal medulla, corresponding with the nucleus tractus solitarius and paratrigeminal nucleus.\n\n\n\nWe suggest that this lesion explains her isolated new cough and localizes the pathway for \"urge to cough\" to this region of the medulla.", "affiliations": "Department of Neurosurgery, Royal Victoria Hospital, Newcastle, UK. Electronic address: [email protected].;Department of Neurosurgery, Royal Victoria Hospital, Newcastle, UK.", "authors": "Paranathala|Menaka Pasangy|MP|;Mitchell|Patrick|P|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.wneu.2020.09.096", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-8750", "issue": "144()", "journal": "World neurosurgery", "keywords": "Case report; Medulla; Neurogenic cough; Nucleus tractus solitarius; Paratrigeminal nucleus; Urge-to-cough; Vagus", "medline_ta": "World Neurosurg", "mesh_terms": "D000328:Adult; D001139:Arnold-Chiari Malformation; D003371:Cough; D019299:Decompression, Surgical; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008526:Medulla Oblongata; D019635:Neurosurgical Procedures; D011183:Postoperative Complications; D016896:Treatment Outcome", "nlm_unique_id": "101528275", "other_id": null, "pages": "196-198", "pmc": null, "pmid": "32977030", "pubdate": "2020-12", "publication_types": "D002363:Case Reports", "references": null, "title": "Neurogenic Cough Associated with Hyperintensity in Dorsal Medulla: Case Report and Anatomical Discussion.", "title_normalized": "neurogenic cough associated with hyperintensity in dorsal medulla case report and anatomical discussion" }

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{ "abstract": "Tiopronin (TP), a glycine derivative with a free thiol, is extensively used for the treatment of cystinuria. Moreover, TP is usually prescribed as hepatoprotective medicine in China. In the present case, a 36-year-old female who presented with foamy urine and general edema was admitted to the hospital. She had been taking TP for six months to treat drug-induced liver injury due to anti-tuberculosis drugs including isoniazid, rifampicin and pyrazinamide. The urine tests at admission revealed nephritic-range proteinuria with a daily urinary protein level of 8,024 mg. Meanwhile, albumin and cholesterol levels were abnormal. The light microscopy was negative and electron microscopy showed foot process effacement. Thus, minimal change disease (MCD) was diagnosed, and TP was consequently discontinued. Finally, the patient accomplished complete remission within five weeks after the cessation of TP without undergoing glucocorticoid therapy. TP was speculated to play an antigenic role in this adverse effect. To date, there are only two similar cases documented in the literature. Herein, we first report a case of a Chinese patient who generated MCD after prolonged TP administration. Clinicians should be wary of the occurrence of MCD due to TP when administering long-term therapy of TP. A weekly urinalysis may be useful for early identification of TP-induced MCD.", "affiliations": "Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.;Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.", "authors": "Zhong|Han|H|;Wang|Ling|L|;Gu|Zhi-Chun|ZC|;Cui|Min|M|;Liu|Xiao-Yan|XY|;Pang|Xiao-Yun|XY|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/atm.2019.07.42", "fulltext": null, "fulltext_license": null, "issn_linking": "2305-5839", "issue": "7(16)", "journal": "Annals of translational medicine", "keywords": "Minimal change disease (MCD); adverse drug reaction; nephrotic syndrome (NS); tiopronin (TP)", "medline_ta": "Ann Transl Med", "mesh_terms": null, "nlm_unique_id": "101617978", "other_id": null, "pages": "398", "pmc": null, "pmid": "31555712", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": "10073167;11494716;15602663;15865542;2057710;20924604;21297330;2138812;2225561;2250412;23631305;24190152;24488902;25026975;25296595;25684013;26330362;2812476;29851774;30051231;3516496;3873945;470014;7158085;7249508;748588;8162007;8242033;9796255", "title": "Minimal change disease induced by tiopronin: a rare case report and a review of the literature.", "title_normalized": "minimal change disease induced by tiopronin a rare case report and a review of the literature" }

[ { "companynumb": "CN-MICRO LABS LIMITED-ML2019-02765", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TIOPRONIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG THREE TIMES DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "UNEVALUABLE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201609", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOPRONIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205600", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG QD PO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG QD PO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PASINIAZID" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG TID PO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PASINIAZID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG ORALLY TWICE WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glomerulonephritis minimal lesion", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZHONG H, WANG L, GU Z, CUI M, LIU X, PANG X. MINIMAL CHANGE DISEASE INDUCED BY TIOPRONIN: A RARE CASE REPORT AND A REVIEW OF THE LITERATURE. ANNALS OF TRANSLATIONAL MEDICINE. 2019?7 NO.16:.", "literaturereference_normalized": "minimal change disease induced by tiopronin a rare case report and a review of the literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20191023", "receivedate": "20191023", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16949052, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "Bilateral intraocular inflammation and simultaneous development of tattoo granulomas has been described in several case reports. The pathophysiology of this process is poorly understood, and it has been hypothesized that it could be a similar mechanism to systemic sarcoidosis versus a delayed hypersensitivity response. Granulomatous tattoo reaction with associated uveitis can manifest with or without evidence of systemic sarcoidosis, and it is usually responsive to immunosuppression and/or tattoo removal. We present a patient with no prior diagnosis of sarcoidosis who developed bilateral panuveitis and tattoo changes suggestive of tattoo granulomas with uveitis (TAGU). The patient was initially managed with intraocular steroids and systemic steroids with minimal improvement of symptoms. The patient later required steroid sparing therapy with a tumor factor inhibitor to achieve remission. There is a growing prevalence of tattooing among the general population and a low reported rate of tattooing complications. Granulomatous tattoo reaction with associated uveitis should be a consideration in patients with tattoos presenting with \"idiopathic\" uveitis.", "affiliations": "University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.;University of Colorado, Denver, CO, USA.", "authors": "Carvajal Bedoya|Guiset|G|0000-0002-3152-7855;Caplan|Liron|L|;Christopher|Karen L|KL|;Reddy|Amit K|AK|0000-0002-5097-823X;Ifantides|Cristos|C|", "chemical_list": "D013256:Steroids; D000068879:Adalimumab", "country": "United States", "delete": false, "doi": "10.1177/2324709620975968", "fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n33238758\n10.1177/2324709620975968\n10.1177_2324709620975968\nCase Report\nTattoo Granulomas With Uveitis\nhttps://orcid.org/0000-0002-3152-7855Carvajal Bedoya Guiset MD1 Caplan Liron MD, PhD12 Christopher Karen L. MD1 https://orcid.org/0000-0002-5097-823XReddy Amit K. MD1 Ifantides Cristos MD13 1 University of Colorado, Denver, CO, USA\n2 Rocky Mountain Regional Veterans Affairs\nMedical Center, Denver, CO, USA\n3 Denver Health Medical Center, Denver, CO,\nUSA\nGuiset Carvajal Bedoya, MD, University of Colorado\nSchool of Medicine, Barbara Davis Building—Rheumatology, 1775 Aurora Ct, B115, Aurora, CO\n80045, USA. Email: [email protected]\n25 11 2020 \nJan-Dec 2020 \n8 232470962097596818 9 2020 26 10 2020 31 10 2020 © 2020 American Federation for Medical Research2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Bilateral intraocular inflammation and simultaneous development of tattoo granulomas has\nbeen described in several case reports. The pathophysiology of this process is poorly\nunderstood, and it has been hypothesized that it could be a similar mechanism to systemic\nsarcoidosis versus a delayed hypersensitivity response. Granulomatous tattoo reaction with\nassociated uveitis can manifest with or without evidence of systemic sarcoidosis, and it\nis usually responsive to immunosuppression and/or tattoo removal. We present a patient\nwith no prior diagnosis of sarcoidosis who developed bilateral panuveitis and tattoo\nchanges suggestive of tattoo granulomas with uveitis (TAGU). The patient was initially\nmanaged with intraocular steroids and systemic steroids with minimal improvement of\nsymptoms. The patient later required steroid sparing therapy with a tumor factor inhibitor\nto achieve remission. There is a growing prevalence of tattooing among the general\npopulation and a low reported rate of tattooing complications. Granulomatous tattoo\nreaction with associated uveitis should be a consideration in patients with tattoos\npresenting with “idiopathic” uveitis.\n\nuveitisgranulomatumor necrosis factor-αtattooingpanuveitisRocky Mountain Regional Veterans Affairs Medical Centercover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nSurveys across multiple countries revealed that the prevalence of tattoos in the general\npopulation is approximately 24%. While tattoos are common, adverse reactions after tattooing\nare fairly infrequent, though these incidents are likely to be underreported.1 Granulomatous tattoo reaction with associated uveitis represents one such rare\nadverse reaction. The overall prevalence of this complication is unknown. A recent review of\nthe medical literature reported only 39 patients over a period of 66 years (1952-2018)\nsuffered from granulomatous tattoo reaction with associated uveitis.2 We report the case of a young adult who developed a granulomatous reaction after the\napplication of a large tattoo.\n\nCase Report\nA 32-year-old Caucasian male presented to the Ophthalmology Service at the Rocky Mountain\nRegional Veterans Affairs Medical Center for evaluation of several months of bilateral eye\nredness and blurry vison. Review of systems was notable for simultaneous onset of diffuse\nerythema, tenderness, induration, and pruritus of a large black ink tattoo over the right\narm and chest (Figure 1). This\ntattoo was inked 1 year prior to presentation. He had 2 other tattoos completed 10 years\nbefore, which were unaffected (Figure\n2).\n\nFigure 1. (A) Inflammation and induration of a large black ink tattoo over right arm and chest;\ntattoo was inked 1 year prior to presentation. (B) Resolution of inflammation after\nsystemic steroid use.\n\nFigure 2. (A/B) Unaffected tattoos performed 10 years prior to presentation.\n\nAt the time of initial presentation, ophthalmological examination with slit lamp revealed\nanterior chamber inflammation and iris synechiae. On optical coherence tomography, there was\nevidence of macular edema (Figure\n3). Skin examination was significant for inflammation, induration, and scant\ndesquamation in a pattern that closely matched the borders of the tattoo. Lungs were clear\nto auscultation. The rest of the history and physical examination was unremarkable.\n\nFigure 3. (A) Slit lamp examination of the left eye revealing iris synechia (head arrow). (B)\nOptical coherence tomography of the left eye macula showing macular edema\n(asterisks).\n\nNo clinical or serological evidence for other uveitis-associated diseases was elicited,\nincluding infections, sarcoidosis, or spondylarthritis. Comprehensive metabolic panel,\ncomplete blood count, urinalysis, thyroid stimulating hormone, free T4, ferritin, creatine\nphosphokinase, and aldolase tests were within normal limits. Erythrocyte sedimentation rate\nwas 13 mm/h, and serum angiotensin-converting enzyme concentration was 86 U/L (14-82).\nC-reactive protein, HLA-B27, antinuclear antibody, antineutrophil cytoplasmic antibody\n(including cytoplasmic, perinuclear, and atypical ANCA), lysozyme, QuantiFERON, HIV,\nhepatitis B and C serologies, rheumatoid factor, anticyclic citrullinated peptide\nantibodies, and computed tomography of the chest were all within normal limits. Punch\nbiopsies of the affected skin were obtained. Histological examination revealed granulomatous\ninflammation with associated tattoo ink deposition consistent with foreign body-type\ngranulomatous reaction (Figure 4).\nMelan A immunostain highlighted scattered single junctional benign melanocytes with control\nsamples staining appropriately.\n\nFigure 4. Histology from punch biopsies of the affected skin (hematoxylin and eosin stain at ×4\n[A] and ×20 [B] power) showing evidence of granulomatous inflammation (arrows) with\nassociated tattoo ink deposition (asterisks) consistent with foreign body-type\ngranulomatous reaction.\n\nThe patient was initially treated with topical ocular glucocorticoids without significant\nimprovement. He then required oral methylprednisolone 24 mg daily, tapered to 4 mg daily\nover 6 days. This agent led to rapid resolution of the inflammatory tattoo changes, but not\nof the macular and optic disc edema. A sub-tenon’s triamcinolone injection to both eyes\nresolved his ocular manifestation; however, tapering of his systemic glucocorticoids caused\nhis tattoo manifestations to reappear. Adalimumab at 40 mg subcutaneously every other week\nsatisfactorily terminated all of his symptoms. Unfortunately, after 3 months of therapy,\npatient developed an injection site reaction. Certolizumab 200 mg SQ every 2 weeks was\ninstituted. A follow-up examination 4 months later revealed minimal, if any, subtle\ninflammation in both eyes, mild worsening of the macular edema in his left eye, and visual\nacuity of 20/20 by Snellen chart.\n\nDiscussion\nTattoo granulomas with uveitis is an exclusion diagnosis. Sarcoidosis should always be\nruled out, even after histologic diagnosis. The histopathological diagnosis of sarcoidosis\nis challenging and drawing a definitive conclusion between sarcoidosis and foreign body\nreaction is not always possible. Granulomatous tattoo reaction with associated uveitis\nphysiopathology is not well understood, but multiple hypotheses have been suggested. A\ndelayed hypersensitivity reaction to ink given its toxic, mutagenic, and carcinogenic\ncompounds has been proposed.3 This large antigenic load may trigger this condition in susceptible individuals.1 A second hypothesis proposes a chronic mild antigenic stimulation from the tattoo ink\nleading to systemic granulomatous reaction consistent with sarcoidosis in susceptible individuals.4\n\nGenerally, all patients with TAGU undergo investigation for sarcoidosis. Patients found to\nhave underlying sarcoidosis usually do not have pulmonary involvement, raising the question\nas to whether this represents a different subset of sarcoidosis with a specific\nenvironmental antigen exposure. Patients with TAGU occurring without concurrent sarcoidosis\nare usually younger, and more likely to have black ink used for tattooing. Uveitis occurs\nalmost simultaneously with tattoo reaction, and symptoms present within the first year after tattooing.2 TAGU is usually responsive to immunosuppression or tattoo removal.5\n\nThis case resembles previous reports in that the patient presented with bilateral uveitis\nwith simultaneous cutaneous and ocular manifestations. Also, his tattoo reaction occurred\nafter using black ink. To the best of our knowledge, this is only the second reported case\nin which adalimumab was demonstrated to be resolve the patient’s signs and symptoms. Our\npatient also presented with panuveitis, which differs from previous reports in which\nanterior uveitis prevails.\n\nConclusion\nGranulomatous tattoo reaction with associated uveitis is a rare clinical entity and likely\nto be underdiagnosed. It should be a consideration in all patients presenting with uveitis\nof undetermined cause. Patients should be screened for tattoos, and if present, the tattoos\nshould be examined. Also, patients with tattoo changes must be actively asked for ocular\nsymptoms. With the increasing popularity of art tattooing or permanent makeup tattooing,\nmore cases of TAGU would be expected.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research,\nauthorship, and/or publication of this article: This work was supported in part by the\nRocky Mountain Regional Veterans Affairs Medical Center. The sponsor was not involved in\nthe design and conduct of the study; collection, management, analysis, and interpretation\nof data; preparation, review, or approval of the manuscript; and the decision to submit\nthe manuscript for publication.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case\nseries.\n\nInformed Consent: Written informed consent was obtained from the patient(s) for their anonymized\ninformation to be published in this article.\n\nORCID iDs: Guiset Carvajal Bedoya \nhttps://orcid.org/0000-0002-3152-7855\n\nAmit K. Reddy \nhttps://orcid.org/0000-0002-5097-823X\n==== Refs\nReferences\n1 \nWenzel S Rittmann I Landthaler M Bäumler W. \nAdverse reactions after tattooing: review of the literature and comparison\nto results of a survey\n. Dermatology .\n2013 ;226 :138 -147\n.23689478 \n2 \nKluger N. \nTattoo-associated uveitis with or without systemic sarcoidosis: a\ncomparative review of the literature\n. J Eur Acad Dermatol\nVenereol .\n2018 ;32 :1852 -1861\n.29763518 \n3 \nRorsman H Brehmer-Andersson E Dahlquist I , et al\nTattoo granuloma and\nuveitis\n. Lancet .\n1969 ;2 :27 -28\n.4182795 \n4 \nSepehri M Hutton Carlsen K Serup J. \nPapulo-nodular reactions in black tattoos as markers of sarcoidosis; study\nof 92 tattoo reactions from a hospital material\n.\nDermatology .\n2016 ;232 :679 -686\n.28166524 \n5 \nOstheimer TA Burkholder BM Leung TG Butler NJ Dunn JP Thorne JE. \nTattoo-associated uveitis\n. Am J\nOphthalmol . 2014 ;158 :637-643.e1.\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2324-7096", "issue": "8()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "granuloma; panuveitis; tattooing; tumor necrosis factor-α; uveitis", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D001706:Biopsy; D005549:Foreign-Body Reaction; D015745:Granuloma, Foreign-Body; D006801:Humans; D008269:Macular Edema; D008297:Male; D013256:Steroids; D013653:Tattooing; D014605:Uveitis; D014792:Visual Acuity", "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709620975968", "pmc": null, "pmid": "33238758", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "28166524;29763518;4182795;24875002;23689478", "title": "Tattoo Granulomas With Uveitis.", "title_normalized": "tattoo granulomas with uveitis" }

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{ "abstract": "Dabigatran is a direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation. The procedure to manage dabigatran-associated haemorrhages is not well formalized. Conventional haemodialysis has been evaluated with good results. Patients with dabigatran-associated bleeding may be unstable and convective techniques like venovenous haemodiafiltration (HDF) can be interesting. We report the case of a 74-year-old, critically ill patient with haemorrhagic shock and dabigatran overexposure due to acute kidney injury. He underwent HDF and dabigatran blood concentrations decreased from 325.3 ng/mL to 160.5 ng/mL. We report here key pharmacokinetics parameters (half-life, extraction coefficient, clearance).", "affiliations": "Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Pharmacology , University Hospital of Saint Etienne , Saint Priest en Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.;Department of Nephrology , University Hospital of Saint Etienne , Saint Priest En Jarez , France.", "authors": "Claisse|Guillaume|G|;Delavenne|Xavier|X|;Masson|Ingrid|I|;Maillard|Nicolas|N|;Alamartine|Eric|E|;Mariat|Christophe|C|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ckj/sfv001", "fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 2581517710.1093/ckj/sfv001sfv001ContentsHaemodiafiltrationVenovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit Claisse Guillaume 1Delavenne Xavier 2Masson Ingrid 1Maillard Nicolas 1Alamartine Eric 1Mariat Christophe 11 Department of Nephrology, University Hospital of Saint Etienne, Saint Priest En Jarez, France2 Department of Pharmacology, University Hospital of Saint Etienne, Saint Priest en Jarez, FranceCorrespondence to: Guillaume Claisse; E-mail: [email protected] 2015 24 1 2015 24 1 2015 8 2 199 201 22 7 2014 2 1 2015 © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] is a direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation. The procedure to manage dabigatran-associated haemorrhages is not well formalized. Conventional haemodialysis has been evaluated with good results. Patients with dabigatran-associated bleeding may be unstable and convective techniques like venovenous haemodiafiltration (HDF) can be interesting. We report the case of a 74-year-old, critically ill patient with haemorrhagic shock and dabigatran overexposure due to acute kidney injury. He underwent HDF and dabigatran blood concentrations decreased from 325.3 ng/mL to 160.5 ng/mL. We report here key pharmacokinetics parameters (half-life, extraction coefficient, clearance).\n\ndabigatran overexposurehaemodiafiltrationhaemorrhagic shockintensive care\n==== Body\nContext\nDabigatran is a direct thrombin inhibitor indicated in prevention of thromboembolic disease in patients with non-valvular atrial fibrillation [1]. Contrary to vitamin K antagonists, no specific blood monitoring is recommended for dabigatran even if there is a real risk of accumulation in the case of renal impairment [2–4]. Importantly, there is no specific antidote of dabigatran. Presently, the procedure to reverse dabigatran in the case of life-threatening bleeding or in situations where urgent surgery is required is not well formalized. It is suggested to use procoagulant drugs [5, 6]. Additionally, based on the characteristics of dabigatran (small molecular weight of 630 Da and low binding to proteins, 30%), haemodialysis is proposed [7].\n\nPrevious studies have focused on removal of dabigatran using conventional haemodialysis, with good results [7–16]. Conventional dialysis usually means a diffusive method with high blood flow (∼350 mL/min), arteriovenous fistula and high dialysate rate (∼500 mL/min). Not rarely, patients with life-threatening bleeding need to be hospitalized in the intensive care unit (ICU) where conventional techniques are not always available. Furthermore, patients with massive bleeding can be haemodynamically unstable and conventional haemodialysis in this context may not be well tolerated. For these reasons, the use of convective-based renal replacement therapy (RRT) like haemodiafiltration (HDF) may have a place in the management of patients with undesirable blood concentration of dabigatran. However, very few data exist on the ability of those techniques to efficiently remove dabigatran from blood [17].\n\nWe report here the case of a patient admitted to the ICU for life-threatening bleeding in the context of dabigatran overexposure managed by HDF.\n\nCase report\nA 74-year-old man was presented to the emergency department with epigastric pain, asthaenia and drowsiness. He had a past medical history of chronic heart failure, chronic subdural haematoma, atrial fibrillation and chronic kidney disease stage 3b and received dabigatran 75 mg twice daily. He took his last dose of dabigatran 7 h before the admission. He was somnolent but arousable, confused with Glasgow Coma Scale 14, haemodynamically unstable with hypotension (95/51 mmHg), mottled skin and tachycardia (100 bpm). Mucocutaneous pallor was noted but without external bleeding. First biology results found anaemia with haemoglobin 7 g/dL (versus 11.5 g/dL two weeks before) and creatinine 276 µmol/L (versus 150 µmol/L usually) i.e. acute kidney injury stage 1 KDIGO. Plasma coagulation was abnormal with prothrombin ratio (PR) 28% and activated partial thromboplastin time (aPTT) 66 s. Blood dabigatran level was 534.9 ng/mL. Brain computed tomography found chronic subdural haematoma without acute bleeding. The patient received 3 packed red blood cells and 1000 mL of intravenous fluids (sodium chloride 0.9%). Upper gastrointestinal endoscopy was realized, finding stomach ulcer with acute bleeding. He was treated by local epinephrine injection and clipping with good efficiency. Continuous infusion by proton pump inhibitor was started (omeprazole 8 mg/h). He did not receive procoagulants drugs. The patient was hospitalized in ICU for RRT.\n\nIn ICU, a dialysis catheter (Blue FlexTip Catheter, 2 lumen, 16 cm, 12 Fr - ARROW®) was inserted in the right internal jugular vein. The patient was started on 4 h of HDF on PRISMA FLEX System (GAMBRO®) with a high-flux dialysis filter (Multiflow 60 AN69HF 0.60 m2 polyacrylonitrile hollow-fibre membrane). The blood (Qb), dialysate (Qd) and ultrafiltration (Quf) flow rates were 200 mL/min, 1 L/h and 3 L/h, respectively. Substitution fluids were delivered in predilution (1 L/h) and in postdilution (2 L/h) with zero net ultrafiltration. Dabigatran levels were sampled every 20 min in blood (inlet line) and effluent (ultrafiltration and dialysate volume collected every 20 min). Dabigatran level was measured by validated liquid chromatography tandem mass spectrometry method. The patient remained awake and alert for the entire session, without external bleeding. Diuresis was 250 mL on 8 h with residual clearance of creatinine measured at 14 mL/min. Dabigatran plasma concentration was 325.3 ng/mL at the beginning of RRT. It decreased gradually during the session to reach 160.5 ng/mL after 4 h (Figure 1). Decrease of dabigatran during HDF was of 25% at 2 h and 51% at 4 h. Conversely, the effluent level of dabigatran increased to reach 138.5 ng/mL at the end of the session. In parallel, aPTT decreased from 180 s at the initiation of HDF to 57.8 s 4 h after the session and PR increased from 30 to 41%. The patient did not receive any drugs that could have interfered with clotting time.\nFig. 1. Plasma and effluent dabigatran during HDF session. Black line represents dabigatran plasma concentrations; grey line represents dabigatran effluent concentration.\n\n\n\nMean haemodiafiltration clearance of dabigatran (Cl(hdf)) was 48 mL/min. Cl(hdf) was measured every 20 min using the recovery method according to the following equation Cl(hdf) = EV/P where E = effluent concentration of dabigatran, V = effluent rate and P = dabigatran plasma concentration. The half-life of dabigatran was 4.8 h. Only the terminal half-life was determined according to the following equation T1/2 = ln(2)/lambda(z) where lambda(z) is the slope of the terminal portion of the log transform concentrations versus time. This was obtained by unweighted linear regression of at least three concentrations.\n\nA rebound of concentrations of dabigatran was observed with a plasma level at 195.7 ng/mL 2 h after the end of the HDF session. Six hours after the HDF session, dabigatran concentration decreases to reach 11 ng/mL probably due to renal recovery. Because of renal recovery, clotting time improvement and decrease of dabigatran levels, no other dialysis session was realized.\n\nThe following day, haemoglobin was 8.6 g/dL. Control endoscopy was realized with a new clipping because of minimal bleeding. Renal function recovered with serum creatinine 168 µmol/L. Coagulation parameters continued to improve with PR 76% and aPTT 37 s at the patient's discharge. After cardiologic consultation, dabigatran was discontinued, replaced by aspirin because of a major risk of bleeding compared with the thromboembolic risk. The patient was discharged to home after 8 days.\n\nDiscussion\nThis case report focused on the interest of convective-based RRT in dabigatran-associated bleeding. In our report, dabigatran blood level decreased from 325.3 to 160.5 ng/mL with a 4-h session of HDF equivalent to a decrease of 51% of dabigatran. This correlated with clotting time improvement. Dabigatran half-life during HDF session was 4.8 h. This figure has to be compared with an expected half-life of 28 h in this patient with glomerular filtration rate (GFR) below 30 mL/min [8]. Thus, the half-life during HDF session is <25% of the half-life off therapy which by definition confirms that dabigatran is effectively removed by HDF [18].\n\nSeveral studies have previously reported the efficacy of haemodialysis techniques to clear dabigatran in different situations. Stangier et al. [8] found an extraction coefficient of dabigatran after 4 h of conventional haemodialysis at 68%, and Khadzhynov et al. [9] reported extractions ratios >45%. Other cases have been reported with comparable results [11–16]. More recently, Singh et al. [12] published on their experience of five cases of acute bleeding associated to dabigatran. All patients received conventional haemodialysis with a decrease of dabigatran ranging from 52 to 77%. In his study, an additional RRT session because of a rebound of dabigatran concentrations was performed using continuous venovenous haemodiafiltration (CVVHDF) apparently with a good result but very few data are given. Regarding the efficacy of convective techniques, Chiew et al. reported on a 66-year-old man treated by 32 h of CVVHDF for dabigatran overdose. They found a mean extraction ratio of 0.2% and a mean dabigatran clearance of 58.1 mL/min using the recovery method [17].\n\nThis case report is a prototype of a patient requiring intensive care, with acute bleeding due to dabigatran overdose. Importantly, we provide here full pharmacokinetic analyses allowing an evaluation of key pharmacokinetic parameters (clearance, half-life).\n\nOur work has other limitations. Decrease of dabigatran (51%) is less important than when conventional dialysis is used (50–80%), probably because of a low dialysate flow rate (1 L/h) and the small surface area of the filter (0.6 square metre). The absence of urine samples did not allow a direct evaluation of renal clearance of dabigatran but as the patient was oliguric we believed that renal excretion of dabigatran was negligible. The difference between dabigatran levels at the admission (534.9 ng/mL) and at the initiation of HDF (325.3 ng/mL) has probably more to do with haemodilution than renal excretion since the patient received three packed red blood cells and 1000 mL of saline solution before the beginning of HDF. The fact that the drug was not at steady-state when dialysis was started and the large distribution volume of dabigatran (70%) [7] can explain the relative increase of blood dabigatran concentrations during HDF session. Although thrombin time (TT) assay is the best test to assess dabigatran activity, it was not available in the emergency ward in our hospital. However, aPTT can be used for a qualitative assessment of dabigatran exposure, and some authors described a good correlation between aPTT and dabigatran concentrations [12].\n\nIn conclusion, this case report suggests that HDF may be an efficient approach for dabigatran removal and can be performed in the case of unstable, critically ill patients with dabigatran overexposure.\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 Connolly SJ Ezekowitz MD Yusuf S \nDabigatran versus warfarin in patients with atrial fibrillation . N Engl J Med \n2009 ; 361 : 1139 –1151 19717844 \n2 Stangier J \nClinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate . Clin Pharmacokinet \n2008 ; 47 : 285 –295 18399711 \n3 Stangier J Clemens A \nPharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor . Clin Appl Thromb Hemost \n2009 ; 15 (Suppl 1) : S9 –16 \n4 Liensenfeld K-H Lehr T Dansirikul C \nPopulation pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial . J Thromb Haemost \n2011 ; 9 : 2168 –2175 21972820 \n5 Ganetsky M Babu KM Salhanick SD \nDabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant . J Med Toxicol \n2011 ; 7 : 281 –287 21887485 \n6 Alikhan R Rayment R Keeling D \nThe acute management of haemorrhage, surgery and overdose in patients receiving dabigatran . Emerg Med J \n2014 ; 31 : 163 –168 . Epub 2013 Feb 22 23435652 \n7 McLellan AJ Schlaich MP \nDabigatran elimination: is haemodialysis effective? \nThromb Haemost \n2013 ; 109 : 580 –581 23389392 \n8 Stangier J Rathgen K Stähle H \nInfluence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study . Clin Pharmacokinet \n2010 ; 49 : 259 –268 20214409 \n9 Khadzhynov D Wagner F Formella S \nEffective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease . Thromb Haemost \n2013 ; 109 : 596 –605 23389759 \n10 Warkentin TE Margetts P Connolly SJ \nRecombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding . Blood \n2012 ; 119 : 2172 –2174 22383791 \n11 Chang DN Dager WE Chin AI \nRemoval of dabigatran by hemodialysis . Am J Kidney Dis \n2013 ; 61 : 487 –489 23219111 \n12 Singh T Maw TT Henry BL \nExtracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience . Clin J Am Soc Nephrol \n2013 ; 8 : 1533 –1539 . Epub 2013 May 23 23704302 \n13 Chen BC Sheth NR Dadzie KA \nHemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose . Am J Kidney Dis \n2013 ; 62 : 591 –594 23597859 \n14 Esnault P Gaillard PE Cotte J \nHaemodialysis before emergency surgery in a patient treated with dabigatran . Br J Anaesth \n2013 ; 11 : 776 –777 23650254 \n15 Wanek MR Horn ET Elapavaluru S \nSafe use of hemodialysis for dabigatran removal before cardiac surgery . Ann Pharmacother \n2012 ; 46 : e21 22872748 \n16 Bachellerie B Ruiz S Conil JM \nPatient with acute renal injury presenting dabigatran overdose: hemodialysis for surgery . Ann Fr Anesth Reanim \n2013 ; 33 : 44 –46 24378048 \n17 Chiew AL Khamoudes D Chan B \nUse of continuous veno-venous haemodiafiltration therapy in dabigatran overdose . Clin Toxicol (Phila) \n2014 ; 52 : 283 –287 24666338 \n18 Lavergne V Nolin TD Hoffman RS \nThe EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology . Clin Toxicol (Phila) \n2012 ; 50 : 403 –413 22578059\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2048-8505", "issue": "8(2)", "journal": "Clinical kidney journal", "keywords": "dabigatran overexposure; haemodiafiltration; haemorrhagic shock; intensive care", "medline_ta": "Clin Kidney J", "mesh_terms": null, "nlm_unique_id": "101579321", "other_id": null, "pages": "199-201", "pmc": null, "pmid": "25815177", "pubdate": "2015-04", "publication_types": "D016428:Journal Article", "references": "23435652;23219111;24378048;23389759;20214409;22578059;22383791;19717844;23650254;23704302;18399711;23389392;21887485;19696042;24666338;21972820;22872748;23597859", "title": "Venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit.", "title_normalized": "venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit" }

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{ "abstract": "We report a case of a previously healthy woman in her early 70s who presented with 2 weeks of episodic abdominal pain and significant weight loss. Imaging of her abdomen revealed acute right ovarian torsion associated with bilateral ovarian enlargement and an indeterminant pelvic mass. An urgent laparoscopic bilateral oophorectomy was performed with pathological results consistent with triple-hit high-grade B-cell lymphoma. She was successfully treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, intrathecal methotrexate and venetoclax with complete remission after three cycles. Ovarian lymphoma is a rare entity and its genetic features have not been well described. We performed a literature review, describe the current knowledge regarding ovarian lymphoma and its therapeutic implication in the genomic age.", "affiliations": "Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA [email protected].;Department of Radiology, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.;Department of Pathology, Mount Auburn Hospital, Cambridge, Massachusetts, USA.;Department of Hematology and Oncology, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.", "authors": "Osataphan|Soravis|S|;Augustynowicz|Aleksandra|A|;Perrino|Carmen|C|;Lam|Prudence|P|", "chemical_list": "D000069283:Rituximab; D014750:Vincristine", "country": "England", "delete": false, "doi": "10.1136/bcr-2021-242423", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(5)", "journal": "BMJ case reports", "keywords": "gynaecological cancer; haematology (incl blood transfusion)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D010051:Ovarian Neoplasms; D000082843:Ovarian Torsion; D000069283:Rituximab; D014750:Vincristine", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "34059546", "pubdate": "2021-05-31", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Triple-hit high-grade B-cell lymphoma presenting with ovarian torsion.", "title_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", 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"drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": 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"VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", 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"drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, 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}, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": "089340", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENETOCLAX" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "3", "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "INHALER", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALBUTAMOL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203856", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "080352", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "203856", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "074290", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080352", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REPORTS. 2021?14(5):ARTICLE NUMBER E242423. DOI:10.1136/BCR?2021?242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20210629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19469637, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-SPO/USA/21/0136729", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "208657", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", 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"drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REP. 2021?14(5):UNK?UNK. DOI:10.1136/BCR?2021?242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210629", "receivedate": "20210629", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19469946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-067545", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INHALER", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBUTEROL [SALBUTAMOL]" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ?CASE?REP. 2021?14(5):E242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210709", "receivedate": "20210709", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19511216, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-PFIZER INC-2021759701", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050467", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK, 1 CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "761103", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "761103", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1 CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1 CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIPITOR" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK,1 CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 1 CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": null, "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALBUTAMOL" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN, S.. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENETOCLAX." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motor neurone disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": 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TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. 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TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION.. BMJ?CASE?REP. 2021?14(5):E242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210630", "receivedate": "20210630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19478090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-SAGENT PHARMACEUTICALS-2021SAG001497", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "1", "drugadministrationroute": 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"drugenddateformat": null, "drugindication": "TRIPLE HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P.. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ?CASE?REP. 2021?14(5)", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210712", "receivedate": "20210712", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19521131, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-304451", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6?CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "5", "activesubstance": { 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REP. 2021?14:E242423 (1?7)", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210721", "receivedate": "20210721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19587993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-ACCORD-229808", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "042", 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HIT LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Taste disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oral pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysphonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrooesophageal reflux disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vocal cord paralysis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Peripheral motor neuropathy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSATAPHAN S, AUGUSTYNOWICZ A, PERRINO C, LAM P. TRIPLE?HIT HIGH?GRADE B?CELL LYMPHOMA PRESENTING WITH OVARIAN TORSION. BMJ CASE REPORTS. 2021?14(5):ARTICLE NUMBER E242423. DOI:10.1136/BCR?2021?242423", "literaturereference_normalized": "triple hit high grade b cell lymphoma presenting with ovarian torsion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210702", "receivedate": "20210702", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19486433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Peritoneal dialysis treatment generates significant amounts of waste for disposal from patients' homes. In Australia, in the days after the onset of the COVID-19 pandemic, waste collection from homes was temporarily stopped. Our patient tried to dispose of his waste by burning the used bags and tubing, using paint thinner as an accelerant. We present a case report of the unusual neurological complication he developed.", "affiliations": "Department of Nephrology, 4435Launceston General Hospital, Tasmania, Australia.;Department of Nephrology, 4435Launceston General Hospital, Tasmania, Australia.;Department of Nephrology, 4435Launceston General Hospital, Tasmania, Australia.", "authors": "Dang|Minh Huan|MH|0000-0001-5612-107X;Rodman|Bodie|B|;Raj|Rajesh|R|", "chemical_list": "D012997:Solvents; D014050:Toluene", "country": "United States", "delete": false, "doi": "10.1177/0896860820965025", "fulltext": null, "fulltext_license": null, "issn_linking": "0896-8608", "issue": "41(1)", "journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis", "keywords": "COVID-19; myoclonus; paint thinner; peritoneal dialysis", "medline_ta": "Perit Dial Int", "mesh_terms": "D001315:Australia; D000086382:COVID-19; D003140:Communicable Disease Control; D004781:Environmental Exposure; D005390:Fires; D006361:Heating; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D009207:Myoclonus; D010530:Peritoneal Dialysis; D012997:Solvents; D014050:Toluene", "nlm_unique_id": "8904033", "other_id": null, "pages": "101-103", "pmc": null, "pmid": "33499779", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Unexpected sequelae of the COVID-19 pandemic: A strange case of myoclonus in the Tasmanian winter.", "title_normalized": "unexpected sequelae of the covid 19 pandemic a strange case of myoclonus in the tasmanian winter" }

[ { "companynumb": "AU-BAXTER-2020BAX014829", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM CHLORIDE\\DEXTROSE\\MAGNESIUM CHLORIDE\\SODIUM CHLORIDE\\SODIUM LACTATE" }, "drugadditional": "3", "drugadministrationroute": "033", "drugauthorizationnumb": "017512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR PERITONEAL DIALYSIS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PERITONEAL DIALYSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIANEAL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Illness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Accidental exposure to product", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200715" } }, "primarysource": { "literaturereference": "DANG M, RODMAN B, RAJ R. UNEXPECTED SEQUELAE OF THE COVID?19 PANDEMIC: A STRANGE CASE OF MYOCLONUS IN THE TASMANIAN WINTER. PERITONEAL DIALYSIS INTERNATIONAL. 2021?41(1):101?103.", "literaturereference_normalized": "unexpected sequelae of the covid 19 pandemic a strange case of myoclonus in the tasmanian winter", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20210219", "receivedate": "20200724", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18068962, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]

{ "abstract": "The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies--infliximab (IFX), adalimumab (ADA) in Crohn's disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17--were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4-25) and 2.4 (95% CI 1.2 - 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1-2); p=0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.", "affiliations": "Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Computer Science and Statistics, Poznan University of Medical Sciences, Dabrowskiego Street 79, 60-529 Poznan, Poland.;Department of General Radiology, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.;Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland.", "authors": "Eder|Piotr|P|;Michalak|Michal|M|;Katulska|Katarzyna|K|;Lykowska-Szuber|Liliana|L|;Krela-Kazmierczak|Iwona|I|;Stawczyk-Eder|Kamila|K|;Klimczak|Katarzyna|K|;Szymczak|Aleksandra|A|;Linke|Krzysztof|K|", "chemical_list": "D000911:Antibodies, Monoclonal; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1038/srep10223", "fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group srep1022310.1038/srep10223ArticleMagnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn’s disease treated with anti-tumor necrosis factor antibodies Eder Piotr a1Michalak Michal 2Katulska Katarzyna 3Lykowska-Szuber Liliana 1Krela-Kazmierczak Iwona 1Stawczyk-Eder Kamila 1Klimczak Katarzyna 1Szymczak Aleksandra 1Linke Krzysztof 11 Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Poland2 Department of Computer Science and Statistics, Poznan University of Medical Sciences, Dabrowskiego Street 79, 60-529 Poznan, Poland3 Department of General Radiology, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, Przybyszewskiego Street 49, 60-355 Poznan, Polanda [email protected] 05 2015 2015 5 1022304 12 2014 07 04 2015 Copyright © 2015, Macmillan Publishers Limited2015Macmillan Publishers LimitedThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies - infliximab (IFX), adalimumab (ADA) in Crohn’s disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17 - were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4 – 25) and 2.4 (95% CI 1.2 – 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1 – 2); p = 0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.\n==== Body\nThe introduction of anti-tumor necrosis factor alpha (anti-TNF) antibodies to the treatment of inflammatory bowel diseases (IBD) is considered to be one of the most important advances in gastroenterologic therapeutics in recent years. It has significantly improved the therapeutic possibilities especially in Crohn’s disease (CD) and changed the understanding of new treatment goals (mucosal healing, deep remission, steroid-free remission) in IBD1. However, there are still many questions as to when and how to treat patients with anti-TNFs. An important limitation of anti-TNF therapy is the loss of response to treatment over time2. In order to optimize the therapy and to improve its efficacy, individualization of therapeutic schedules has been proposed. The measurement of drug trough levels and anti-drug neutralizing antibodies allows for the modification of the treatment algorithms, which can lead to better long-term therapeutic outcomes, higher mucosal healing rates and less surgery3. Another possibility of treatment optimization is the appropriate selection of patients for anti-TNF therapy. Several predictors of a good response to anti-TNF agents or treatment failure have been described4. However, results from different studies concerning this aspect of the optimization of anti-TNF therapy are conflicting.\n\nThe development of new cross-sectional imaging techniques such as magnetic resonance enterography (MRE) has, in recent years, significantly improved the possibilities of assessing the activity of the small bowel in CD5. One of the most important advantages of MRE is that it enables the visualization of the whole spectrum of inflammatory lesions in CD – endoluminal, mural and extramural. Thus, MRE is helpful in describing CD phenotype and behavior according to the CD Montreal classification, which defines the disease location in the gastrointestinal tract and differentiates between luminal, penetrating, and stricturing forms of the disease6. Moreover, the non-invasive nature of MRE and the lack of radiation exposure allow for the repeated performance of this investigation, thereby enabling the dynamic assessment of CD progression or regression in time. This is particularly important in the monitoring of patients undergoing anti-TNF therapy.\n\nThe usefulness of MRE in CD diagnostics has been proved in many studies567. Moreover, there is an increasing number of scoring systems quantifying CD activity in MRE8910. It has been also shown, that MR imaging can be very helpful in monitoring anti-TNF therapy in CD patients111213. However, little is known whether MRE assessment can be helpful in predicting the response to anti-TNF therapy. In this study, we performed a retrospective analysis of the possible role of MRE in predicting long-term and steroid-free remission in patients with CD treated with biological agents, who initially responded to induction doses of anti-TNF antibodies. We also analyzed which MRE parameters can predict secondary non-response in this group of patients.\n\nResults\nAmong 90 patients treated with anti-TNF antibodies, 61 (68%) were primary responders (40 treated with IFX and 21 treated with ADA) and they comprised the final study group. All further analyses concerning the usefulness of different radiological, and biochemical parameters in predicting one-year efficacy of anti-TNF therapy corresponded to this group of patients.\n\nThere was a slight predominance in the number of female CD patients, mean disease duration was 6 ± 4 years. Biochemical analyses showed elevated inflammatory markers, like C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR). Median CDAI was 267 points (95%CI: 232 – 292), which corresponded to a moderate clinical activity of CD. Almost 40% of patients underwent surgery in the past because of CD. The majority of patients demonstrated an inflammatory phenotype of CD. Full characteristics of the whole study group is presented in Table 1.\n\n44/61 (72%) patients reached the primary therapeutic end point, and 17/61 (28%) patients were classified as secondary non-responders. Secondary non-responders had significantly higher baseline CRP concentrations and higher platelet (PLT) counts when compared with patients who achieved steroid-free remission at week 52. Patients with longer disease duration and previous surgery were more probable to experience a secondary loss of response to anti-TNF therapy, however these differences were not statistically significant. In contrast to that, inflammatory phenotype of CD was significantly related to a higher probability of sustaining long-term remission at week 52 in comparison with penetrating and stricturing disease. Comparison between the two aforementioned study subgroups in terms of other biochemical, clinical, radiological and endoscopic features is presented in Table 2.\n\nCalculation of ROC curves showed that none of the MRE features, analyzed separately, had a potential to predict one-year remission in the study group. However, when two features, which are routinely assessed together in daily practice – bowel wall thickening and contrast enhancement - were also statistically analyzed together (range 0 – 4 points), ROC curve showed that they had the potential to predict the achievement of primary therapeutic end point in the study group (p = 0.01; AUC 0.67). An optimal cut-off point was ≥3 points, with 67% (CI 52 – 81%) sensitivity and 65% (CI 39 – 86%) specificity (Fig. 1). Combination analyses of other investigated features did not show any statistical significance.\n\nBinary logistic regression analyses revealed that bowel stenosis (p = 0.01) and the presence of intra-abdominal fistulas (p = 0.004) seen in MRE were significantly related to secondary non-response in the study group (Table 3). Other parameters were not related to a secondary treatment failure. In case of ulcerations the statistical analysis was impossible due to too few cases of ulcerations in the analyzed sample.\n\nFigures 2 and 3 show MRE images illustrating examples of response and non-response to one-year anti-TNF therapy.\n\nDiscussion\nClinical studies have shown that the initial response rate to anti-TNF therapy is approximately 60%. In this group, about 30% of patients maintained remission for up to one year214. Thus, appropriate qualification for biological therapy is essential in order to choose those patients who are the best candidates for anti-TNF treatment. Such patient selection is also important from a pharmacoeconomical point of view, and in order to minimize the risk of developing serious adverse reactions in subgroups of patients, who are already less likely to respond to anti-TNF therapy15.\n\nLittle is still known about which factors predict a good response or failure of anti-TNF therapy in CD. So far, several clinical, biochemical, and genetic parameters have been investigated in order to determine their association with response to anti-TNF agents. It has been hypothesized that the best candidate for anti-TNF therapy is a young, non-smoking patient with short CD duration, colonic disease location, non-stricturing CD behavior, having high CRP concentration and who had not been previously treated surgically4161718. Additionally it seems that the presence of perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and the absence of anti-Saccharomyces cerevisiae antibodies (ASCA) is associated with a failure of anti-TNF therapy19. The utility of several genetic factors in determining the expected efficacy of biologic agents is still questionable420. It should however be pointed out that the majority of the studies cited, referred to the usefulness of the various factors in predicting short-term response to anti-TNF therapy. Little is known about their usefulness in predicting long-term steroid-free remission of CD. We also do not know which factors could be associated with secondary loss of response to biological therapy\n\nAmong other investigations, MRE has in recent years become one of the most frequently used cross-sectional imaging methods in estimating CD behavior and activity5. Although it must be emphasized that, according to the consensus statement of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD), cross-sectional imaging methods (like MRE or ultrasound) have not been validated so far, current European Crohn’s and Colitis Organisation (ECCO) guidelines for imaging techniques in IBD indicate that they can be routinely applied for the assessment of the CD activity. It was also emphasized in the guidelines that MR techniques are especially useful as their diagnostic accuracy is similar to the accuracy of computed tomography, but with the major advantage of not imparting ionizing radiation2122. Thus, it seems to be essential to investigate the usefulness of MRE in predicting anti-TNF treatment efficacy. To the best of our knowledge, our study is one of the first of its type to determine the predictive role of several imaging features seen in MRE in patients with CD qualified for anti-TNF therapy.\n\nSeveral scores quantifying CD activity in MRE have been developed. The majority of them consist of similar MRE parameters, although none of those radiological features is pathognomonic for CD. Some of them can also be seen in other inflammatory small bowel disorders (mainly in gastrointestinal infectious diseases like yersiniosis), and non-inflammatory diseases, like for example small bowel neoplasms or ischemia23. That is why it is important to analyze all radiological features always in the clinical context. The most typical, major MRE features for CD are fat wrapping, an abnormal bowel wall thickness together with a mural hyperenhancement, enlargement and edema of mesenteric lymph nodes5. Another specific feature of CD – ulcerations, can be seen in the case of a full luminal distension, and it concerns only moderate to deep linear ulcers. Superficial, early ulcerations are not well demonstrated at MRE imaging.\n\nIn recent years, development of some new MRE sequences and methods for the assessment of CD activity has taken place. This increases the number of inflammatory parameters defined by MR imaging, among those discussed above. One of the most promising methods is the diffusion-weighted imaging (DWI). DWI reflects the changes in the water mobility caused by interactions with cell membranes, macromolecules, and alterations of the tissue environment24. It was shown that DWI enables detection of inflammatory activity in small bowel and colonic CD and is an accurate tool in assessing the disease activity. However, more studies are needed in this field.\n\nOne of the most well-known scores for “classical” MRE assessment in CD is the Magnetic Resonance Index of Activity (MaRIA) proposed by Rimola et al.8. MaRIA allows to assess the CD activity both in the small and the large bowel. This is due to the fact, that in the aforementioned study the colon was additionally filled with warm water by inserting a flexible rectal balloon catheter, which gave a sufficient large bowel distension810. This is in contrast with the majority of MRE protocols, in which MRE imaging is performed completely noninvasively, focusing on the assessment of the small bowel CD activity. Thus we decided to use a simple score allowing the assessment of CD activity in MRE performed according to a “standard” protocol10. In consequence, we also excluded from our study patients with isolated colonic CD location. The utility of the MRE score used in the current study was proved in an independent group of CD patients, and it correlated significantly with endoscopic activity, which was considered the gold standard for evaluation of CD activity. This score takes into account the most important and frequently assessed radiographic features of CD. Due to its simplicity, it can be easily applicable.\n\nThe statistical analysis revealed that an active inflammatory involvement of the intestine, reflected by bowel wall thickening and contrast enhancement in the baseline MRE were predictive of one-year steroid-free remission at week 52 in patients treated with anti-TNF agents. An optimal cut-off point was ≥3 points. This means that the best candidates for anti-TNF therapy are patients with bowel wall thickening ≥3 mm with a layered enhancement pattern after gadolinium administration or patients with bowel wall thickening >7 mm and any type of contrast enhancement. Additionally, the inflammatory (non-stenosing and non-penetrating) disease behavior was also significantly associated with long-term remission at week 52. These data confirm that high inflammatory burden of CD is associated with a good response to anti-TNF agents2526. However, it is still a matter of debate how to define this inflammatory burden in the case of CD. Nevertheless, patients with all active forms of CD can benefit from anti-TNF therapy, but probably those with high luminal inflammatory activity without complications will have better therapeutic outcomes. Our study is one of the first studies to show that this observation can also be applied to MRE investigations. However, it should be pointed out that only a combined approach including at least two features of MRE activity – presence of lesions with increased contrast enhancement - might indicate positive long-term therapeutic effects.\n\nDue to the increasing number of CD patients treated worldwide with anti-TNF antibodies, the problem of a secondary non-response becomes one of the most important limitations of this therapy2. Optimizing the treatment algorithm by increasing drug doses or by shortening the interval between doses, based on pharmacokinetic analyses, seems to be a valuable option in this clinical situation32728. However, the wide application of drug trough levels monitoring and anti-drug antibodies testing in everyday practice is still not commonly accessible3. Thus, more attention should be paid to the proper selection of patients who have the highest probability of achieving long-term CD remission with biological treatment. Our analysis showed that patients with at least one stenosis with prestenotic bowel dilatation assessed in dynamic sequences had an almost 6-fold higher risk of developing a secondary non-response when compared with patients without stenosis. What is more, even the presence of stenosis without prestenotic dilatation was significantly associated with secondary anti-TNF treatment failure. It should be emphasized that none of the patients with stenoses detected in MRE had radiographic signs of their fibrotic etiology. Additionally none of the patients suffered from obstructive gastrointestinal symptoms before starting the anti-TNF therapy. Current recommendations allow the use of anti-TNF agents in patients with stenotic CD, but only if they are not of a fibrotic origin2930. In fibrostenotic CD, endoscopic dilatation or surgical treatment should be considered31. Our study also shows the probability that patients with non-fibrotic stenoses should not be treated with anti-TNF agents, as they are at a high risk of developing a secondary non-response. Alternatively a more individualized and aggressive treatment algorithm should be introduced in this subgroup of patients, in order to avoid surgery.\n\nThe presence of intra-abdominal fistulas detected in MRE increased also the risk of developing secondary non-response to anti-TNF therapy. Current guidelines do not recommend pharmacological treatment in CD patients with intra-abdominal fistulas, as they should be treated surgically31. Unfortunately, this recommendation cannot always be easily applied in everyday clinical practice. Some patients do not accept surgical treatment, especially when they have undergone one or more bowel resections in the past. In our cohort of patients with intra-abdominal fistulas who initially responded to anti-TNF therapy and then developed secondary non-response (n = 6), all of them either did not initially accept the surgical treatment option or were disqualified from surgery because of other co-morbidities. After secondary failure of anti-TNF therapy, the majority of them (4/6) were treated surgically, and two received total parenteral nutrition (data not shown). Thus, since the efficacy of anti-TNF therapy in patients with intra-abdominal fistulas is poor, it seems that more attention should be paid in convincing patients to undergo surgical or alternative treatment.\n\nAnother observation from our study is that fat wrapping, which is believed to be one of the most characteristic features of an active CD, was not predictive for long-term therapeutic outcomes5. However, the grading score applied for this parameter could be less discriminative in order to differentiate active from inactive inflammatory lesions in MRE. That is why, as this parameter is always assessed together with vascular proliferation in the mesenteric fatty tissue, in order to make this aspect of CD activity estimation in MRE more discriminative, we summed up (scoring range 0–3 points) these two strictly interrelated parameters (fat wrapping and vascular proliferation in the mesenteric fatty tissue). In the first step, we performed an additional statistical analysis in which we divided our study group into three subgroups depending on their BMI results: <18.5 kg/m2 (n = 9), 18.5 – 25 kg/m2 (n = 45), and >25 kg/m2 (n = 7). Comparative analysis revealed no differences in the intensity of fat wrapping and vascular proliferation in those subgroups. Then, after checking that nutritional status does not interfere with the assessment of the discussed MRE parameters, we conducted further statistical analysis in order to estimate whether fat wrapping and vascular proliferation can be predictive for long-term treatment outcomes. The analysis, however, did not show their usefulness to predict the long-term response in our study group (OR for 2 points = 1; 95%CI 0.6 – 1.7, OR for 3 points = 1.3; 95% CI 0.04 – 37.1; p = 0.4). That is why we hypothesize that although this parameter is important for the assessment of CD activity, it seems probably not to have prognostic value.\n\nAnalysis of biochemical data also showed, that patients who were secondary non-responders had a significantly higher baseline CRP concentration. This seems to be in contrast with the results of some other studies. Louis et al. were first to show that a higher CRP level before treatment was associated with a positive clinical response to IFX25. Several other studies revealed that high baseline CRP concentration and its normalization after induction doses of anti-TNF agents were predictive of maintained clinical efficacy of biological therapy152632. On the other hand it has been shown that high CRP levels at the moment of diagnosis are associated with a worse CD course and that they predict the need for surgical treatment33. The most recent study by Magro et al. also showed that a high CRP concentration predicts rather a non-response to therapy with IFX in CD34. Thus, it should be emphasized that data in terms of the predictive role of CRP in anti-TNF therapy are conflicting. One can speculate, that the reason for these differences is probably due to differences in the etiology of CRP elevation. High inflammatory burden reflected by high CRP level is connected with a better outcome of anti-TNF therapy. The presence of CD complications (fistulas, stenoses) which can also lead to CRP elevation is related to a worse efficacy of biological agents. This hypothesis can also explain why patients with a higher baseline PLT count more frequently experienced a secondary non-response to anti-TNF therapy in our study group, as PLT are believed to be one of the most sensitive markers of CD severity35. However, it should be mentioned that although biochemical markers can be helpful, current guidelines emphasize the need of more complex assessment of CD activity by using endoscopy and cross-sectional imaging methods, which allow to estimate the whole spectrum of mucosal and transmural damage36.\n\nOur study has several limitations. The study group was strictly defined and the analyses concerned only primary responders to anti-TNF therapy, thus our data might be biased. Moreover, the number of patients is relatively low, which is due to very strict inclusion and exclusion criteria. This potentially could lead to some statistical misinterpretation of obtained data. Thus, although our study group is still one of the largest in the discussed subject matter, there is an urgent need to confirm the results in larger, prospective trials.\n\nBesides, it is still not fully clear which MRE features should be used in the first line in the assessment of CD activity, and how some of them should be interpreted. Some studies in that matter bring conflicting results. For example it is still being discussed how to define and stratify bowel wall thickening. Cutoff points for differentiation of different CD stages and its activity are still lacking or data are conflicting5. For example, there are some data using 4 mm as a cut off point for an abnormal bowel wall thickness37. It was also shown, that MRE was accurate for grading mural small bowel CD mainly in case of frank disease, and there could be some disease overstaging in the cases of patients in remission or mild CD activity538. Another unanswered question is whether bowel wall thickness requires an adjustment for different body weight or previous abdominal surgery. As there are no data in this field, we tried to analyze if these factors had an impact on CD mural lesions. We did not find any correlation between patients‘ BMI and bowel wall thickness. Moreover, we divided patients according to their BMI into three groups: <18.5 kg/m2 (n = 9), 18.5 – 25 kg/m2 (n = 45), and >25 kg/m2 (n = 7). Additional statistical analysis showed that bowel wall thickness was similar when compared patients with a different BMI. We also divided our study group into patients who underwent surgery in the past, and those without surgery. The median bowel wall thickness was 2 (95%CI 1.5–2.1) and 2 (95%CI 1.7–2) respectively, so the difference was not significant (p = 0.5). That is why we hypothesize that BMI or previous surgery do not influence this MRE parameter. Moreover, in the study performed by Gallego-Ojea et al. in which the usefulness of MRE in the detection of disease recurrence after surgery was shown, the authors also considered bowel wall thickness ≥3 mm as abnormal39. That is why, according to the current guidelines and teaching tutorials for radiologists, we decided to consider bowel wall thickness ≥3 mm as abnormal although some controversies in this field still exist40.\n\nAdditionally, heterogeneous enhancement of the bowel wall after contrast administration, believed to be a sign of active mural inflammation, was also suggested to be associated with fibrostenotic disease541. Moreover, in our study contrast enhancement was rated on a qualitative score. It is also unknown, whether characteristics of an individual patient can interefere with the reading of hyperenhancement in MRE. Although there are no data in this field, we divided our patients once again, depending on the BMI results, into three group, as presented above, and performed an additional statistical analysis. We did not find any association bewteen BMI and the character of contrast enhancement (data not shown). Thus, we hypothesize that this parameter is not related to patients‘ nutritional status.\n\nTo summarize this part of the discussion, we would like to emphasize that all selected MRE features assessed by the radiologist in our study are believed to be the most sensitive in detecting inflammatory activity of CD5678910. Despite some of the controversies presented above, MRE is still a method of choice in diagnosing and monitoring small bowel CD, and the majority of MRE assessment protocols used worldwide consist of very similar features as those assessed in our study.\n\nThe most important limitation of our study is that our MRE images were assessed by a single radiologist, thus, there was no interobserver agreement analysis performed. Moreover, a qualitative assessment of MRE images can be subjective, especially in the case of wall thickness and hyperenhancement quantitation. However, other studies have shown that the agreement between experienced radiologists in MR assessment is high, especially in large university radiological centers42. We would also like to emphasize that our radiologist is highly experienced in this type of MRE technique and was blinded to the anti-TNF efficacy results.\n\nIn summary it should be pointed out that MRE is an adequate tool not only in assessing CD extent and its activity. This cross-sectional imaging technique can also provide valuable prognostic data regarding the expected efficacy of anti-TNF treatment in a CD patient. Thus, it could be helpful in optimizing biological therapy. One of the main limitations of more frequent application of MRE is its relatively high cost. According to British data, the mean cost of MR enteroclysis is £268 and is slightly higher than MRE (£241). CT enterography seems to be the cheapest method, as its cost is £13343. Although costs can differ between countries and even between different departments, greater financial burden of MR imaging is a rule. Thus, some authors suggest that MRE should be performed only in the youngest patients and in other cases CT enterography is preferred. It seems, however, that a proper qualification for anti-TNF therapy can lead to the optimization of this expensive treatment and can lower its costs. Thus, as MRE is believed to be a useful method in the assessment of CD activity, the application of this method in qualification process for anti-TNF therapy could, hypothetically, be economically beneficial2223. The reason for this is that selecting the best candidates for anti-TNF treatment is still challenging, as approximately 30% of all CD patients will lose the initially obtained response to this therapy. Our study showed for one of the first times that MRE is probably useful in this selection process. This could limit toxicity, save costs and allow for the more accurate use of anti-TNF agents. However, in order to undoubtedly confirm these data, and to allow to directly translate them into clinical practice, there is a need for larger prospective trials in which an additional interobserver agreement analysis would be performed, before more widespread implementation of MRE in patients with CD will take place.\n\nMethods\nStudy population\nA retrospective cohort study was performed among patients with CD hospitalized between 2009 and 2012 at the Department of Gastroenterology, Human Nutrition and Internal Diseases at Poznan University of Medical Sciences. The inclusion criteria were as follows:\n\nage ≥18 years\n\nexacerbation of CD ineffectively treated with steroids and/or immunomodulators and meeting the eligibility criteria for anti-TNF therapy\n\nrealisation of MRE in accordance with the same protocol (presented below) 1–14 days before starting anti-TNF therapy\n\nresponse to the induction regimen of anti-TNF therapy with infliximab (IFX) or adalimumab (ADA) according to the criteria defined below, allowing for the continuation of maintenance therapy.\n\nThe exclusion criteria were:\n\nprimary non-response to anti-TNF therapy\n\nneed for any change in treatment regimen during induction doses of anti-TNF therapy\n\nisolated colonic location of CD, in which the diagnostic usefulness of MRE is lower than in ileal or ileocolonic CD\n\ntreatment with IFX or ADA within 52 weeks before enrollment into the study\n\npresence of any general contraindications to MR procedure, such as any metallic medical devices or foreign bodies (for example cardiac pacemaker, implanted cardioverter-defibrillator, joint replacement etc.) or renal insufficiency.\n\nThe clinical activity was routinely assessed by calculating the Crohn’s Disease Activity Index (CDAI)44. Each patient also underwent ileocolonoscopy performed by an experienced endoscopist (KL, IKK, LLS) with the estimation of the Simple Endoscopic Score for Crohn’s Disease (SES-CD)45. Biochemical markers of CD activity were measured routinely.\n\nMRE protocol\nMRE examinations were performed with a 1,5 Tesla clinical unit (Magnetom Avanto, Siemens Medical Solutions, Erlangen, Germany) with six-channel abdominal phased-array coils with a spine matrix coil. Each patient underwent MRE according to the same standard protocol previously described10. Namely, patients fasted for 6 hours before MRE. Patients were then given 1500 ml of oral polyethylene glycol (PEG) electrolyte solution (a single sachet of PEG diluted in 1500 ml of water – Fortrans, Ipsen Pharma) to drink 30–40 minutes before the investigation. Additionally, 40 mg of buscolysin (Hyoscini butylbromidum, Sopharma Plc, Bulgaria) was given intravenously prior to gadolinium administration in order to reduce bowel motility. To reduce respiratory movements and provide higher image quality, all imaging was performed under breath-hold conditions. The standard study protocol consisted of the sequences listed in Table 4.\n\nImage analysis\nThe most important and best studied MRE features of CD activity were assessed and quantified according to the scale proposed in Table 5678910. The usefulness of our score was proved in an independent cohort of CD patients, where it was compared with endoscopy, which is thought to be the gold standard in the assessment of CD activity10. The evaluation of MRE was performed by a single radiologist (KK), who was blinded to the efficacy results of anti-TNF therapy, and who has more than 10 years of experience in this imaging method.\n\nAnti-TNF treatment regimens and definition of therapeutic end points\nAccording to the anti-TNF induction regimen, patients were then given either 3 doses of 5 mg/kg body weight of IFX intravenously at week 0 – 2 – 6, or 160 mg of ADA subcutaneously at week 0, 80 mg at week 2 and 40 mg every other week until week 12.\n\nFollow-up investigations, including ileocolonoscopy, were performed at week 10 in case of IFX and at week 13 in case of ADA. Primary response to anti-TNF therapy was defined as a ≥100 – point decrease in the CDAI score (CDAI-100 response) with concomitant endoscopic improvement (any decrease in the SES-CD score). All primary responders were then placed on the maintenance regimen: 5 mg/kg body weight IFX every 8 weeks or 40 mg ADA every other week until week 52.\n\nThe therapeutic primary end point was clinical and steroid-free remission (CDAI < 150 points) at week 52. All patients who did not reach the therapeutic primary end point (CDAI ≥ 150 points and/or need for reintroducing steroids), and who needed optimization of anti-TNF therapy (increasing the doses or decreasing the intervals between doses) were considered as secondary non-responders. The main aim of the study was to assess which of the MRE parameters assessed during baseline imaging study have the potential to predict one-year steroid-free remission or secondary non-response in patients treated with anti-TNF antibodies.\n\nStatistical analysis\nDescriptive statistics was made by calculating means with standard deviations or medians with 95% confidence intervals. To compare clinical, endoscopic and biochemical data, the Student t test (parametric) was used when conditions of normality and equal variance were met. The Student t test was used with Welch correction when unequal variances were detected. When the normality test failed, a 2-tailed and exact Mann–Whitney rank sum test (nonparametric) was used. The differences in the disease behavior and disease locations in the study subgroups were assessed by using the Chi square test.\n\nEach MRE feature was graded according to the scoring system presented in Table 5 and assessed statistically separately, and – in the next step - in combination with other MRE features. In the second case the results were summarized. Receiver operating characteristic (ROC) curves were calculated to determine the potential of analyzed parameters to differentiate patients who had reached the therapeutic primary end point. An optimal cut-off point was calculated according to the highest accuracy (minimal false negative and false positive results). The area under the ROC curve (AUC) was used to check the prognostic value of particular parameters. For parameters which showed prognostic value, their sensitivity and specificity were additionally calculated.\n\nIn order to determine parameters which could be predictive of secondary loss of response to anti-TNF agents, a binary logistic regression analysis with subsequent cross validation was performed to identify the best discriminating MRE parameters by calculating the percentage overall correct classifications. For all studied parameters, odds ratios (OR) and 95% confidence intervals (CI) were presented.\n\nStatistical analyses were performed with MedCalc version 10.3.2 (MedCalc Software, Mariakerke, Belgium) and Statistica 10 (StatSoft Inc., Poland). All tests were considered significant at a p value of less than 0.05.\n\nThe study was approved by the Bioethics Committee at the Poznan University of Medical Sciences (No 774/13). An informed consent was obtained from all patients. The protocol of this study was performed strictly in accordance with the approved guidelines.\n\nAuthor Contributions\nP.E. designed the study, carried out the study and data analyses and drafted the manuscript. M.M. performed the statistical analyses and helped to draft the manuscript. L.L.S., K.K., I.K.K., K.S.E. helped to design and to revise the manuscript. K.K., A.S. and K.L. helped to revise and drafted the manuscript. All authors read and approved the final manuscript.\n\nAdditional Information\nHow to cite this article: Eder, P. et al. Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn’s disease treated with anti-tumor necrosis factor antibodies. Sci. Rep.\n5, 10233 doi: 10.1038/srep10223 (2015).\n\nWe would like to thank Clinton Muoto and Peter Jones for their perfect writing assistance (funding source for writing assistance: none).\n\nPE, LLS, and KK received lecture fees from Abbvie Poland. Other authors declare no competing financial interests.\n\nFigure 1 Receiver operator characteristic (ROC) curve showing that the score assessing bowel inflammatory thickening with contrast enhancement in the baseline magnetic resonance enterography (range 0 – 4 points) was predictive for long-term steroid-free remission at week 52 in Crohn’s disease patients treated with anti-TNF antibodies. An optimal cut-off point was ≥ 3, and it allowed to predict with 67% (confidence interval: 52 – 81%) sensitivity and 65% (confidence interval: 39 – 86%) specificity achievement of the primary therapeutic end point of the study (p = 0.01; area under the curve 0.67).\n\nFigure 2 Magnetic resonance enterography images illustrating an example of a response to one-year anti-tumor necrosis factor (anti-TNF) therapy in a patient with Crohn’s disease: (a) Week 0 - before anti-TNF therapy. T2-weighted sequence demonstrating thickening of a bowel wall (white arrows) without stenosis of the bowel lumen. (b) Week 0 - before anti-TNF therapy. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating thickening of a bowel wall with enhancing in the various layers of the wall - hyperintense signal corresponding to edema in acute inflammation (white arrows). (c) Week 52. T2-weighted sequence demonstrating decrease of thickening of the bowel wall (white arrows) after one-year anti-TNF therapy. (d) Week 52. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating decrease of thickening of the bowel wall with moderate enhancement typical for moderate activity of inflammation (white arrows) - after one-year anti-TNF therapy.\n\nFigure 3 Magnetic resonance enterography images illustrating an example of a non-response to one-year anti-tumor necrosis factor (anti-TNF) therapy in a patient with Crohn’s disease: (a) Week 0 - before anti-TNF therapy. T2-weighted sequence demonstrating thickening of a bowel wall (white arrows) with stenosis of the bowel lumen with prestenotic dilatation (asterisk). (b) Week 0 - before anti-TNF therapy. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating thickening of a bowel wall with enhancing in the various layers of the wall - hyperintense signal corresponding to edema in acute inflammation and dilatation of lumen (white arrows). (c) Week 52. T2-weighted sequence demonstrating increase of thickening of the bowel wall (white arrow) with stenosis of lumen and prestenotic dilatation (asterisk) after one-year anti-TNF therapy. (d) Week 52. Dynamic contrast enhanced T1-volume interpolated gradient-echo sequence demonstrating increase of thickening of the bowel wall with enhancement typical for activity of inflammation (white arrows) – after one-year anti-TNF therapy.\n\nTable 1 Baseline characteristics of the 61 Crohn’s disease patients, who responded to the induction anti-tumor necrosis factor therapy (primary responders), which comprised the final study group.\nFeature\tn=61\t\nAge [mean ± SD]\t32 ± 10\t\nMale/female\t29/32\t\nDisease duration (years) [mean ± SD]\t6 ± 4\t\nC-reactive protein (mg/l) [mean ± SD]\t22.1 ± 26.1\t\nErythrocyte sedimentation rate (mm/h) [mean ± SD]\t32 ± 20\t\nRed blood cell count (106/mm3) [mean ± SD]\t4.4 ± 0.7\t\nHemoglobin (g/dl) [mean ± SD]\t12.3 ± 2.2\t\nHematocrit (%) [mean ± SD]\t37 ± 5\t\nWhite blood cell count (103/mm3) [mean ± SD]\t7.5 ± 3.7\t\nPlatelets (103/mm3) [mean ± SD]\t358 ± 109\t\nBody mass index (kg/m2) [mean ± SD]\t20.9 ± 3.3\t\nCrohn’s Disease Activity Index [median (95%CI)]\t267 (232 – 292)\t\nSimple Endoscopic Score for CD (SES-CD) [median (95%CI)]\t12 (11 – 18)\t\nIleal SES-CD [median (95%CI)]\t5 (4 – 7)\t\nColonic SES-CD [median (95%CI)]\t8 (7 – 13)\t\nPrevious surgery – n (%)\t24/61 (39%)\t\nDisease location – n (%)\t \t\nL1 (ileal)\t26/61 (43%)\t\nL3 (ileocolonic)\t35/61 (57%)\t\nDisease behavior – n (%)\t \t\nB1 (inflammatory)\t32/61 (53%)\t\nB2 (stricturing)\t10/61 (16%)\t\nB3 (penetrating)\t19/61 (31%)\t\nMedications\t \t\nSteroids\t26/61 (42%)\t\nAzathioprine\t53/61 (87%)\t\nAminosalicylates\t60/61 (98%)\t\nProbiotics\t46/61 (75%)\t\nAntibiotics\t15/61 (24%)\t\nPrevious anti-TNF therapy\t8/61 (13%)\t\nData are presented as means with standard deviations (SD) or medians with 95% confidence intervals (CI).\n\nTable 2 Comparison of baseline data (week 0) of Crohn’s disease patients who achieved one-year steroid-free remission at week 52 (responders) with secondary non-responders group.\nFeature\tResponders\tNon-responders\tp\t\nNumber of patients (%)\tn=44/61 (72%)\tn=17/61 (28%)\t \t\nAge (years) [mean ± SD]\t30 ± 8\t37 ± 13\tns\t\nMale/female –n (%)\t22/22\t7/10\t \t\nDisease duration (years) [mean ± SD]\t5 ± 3\t6 ± 5\tns\t\nC-reactive protein (mg/l) [mean ± SD]\t16.4 ± 15.7\t35.3 ± 38.7\t0.01\t\nErythrocyte sedimentation rate (mm/h) [mean ± SD]\t30 ± 18\t37 ± 23\tns\t\nRed blood cell count (106/mm3) [mean ± SD]\t4.4 ± 0.8\t4.4 ± 0.7\tns\t\nHemoglobin (g/dl) [mean ± SD]\t12.5 ± 2.1\t11.6 ± 2.5\tns\t\nHematocrit (%) [mean ± SD]\t38 ± 5\t36 ± 6\tns\t\nWhite blood cell count (103/mm3) [mean ± SD]\t7.3 ± 3.5\t7.9 ± 4.2\tns\t\nPlatelets (103/mm3) [mean ± SD]\t328 ± 98\t429 ± 103\t0.009\t\nBody mass index (kg/m2) [mean ± SD]\t21.2 ± 3\t20.9 ± 3.3\tns\t\nCrohn’s Disease Activity Index [median (95%CI)]\t264 (220 – 294)\t304 (216 – 331)\tns\t\nSimple Endoscopic Score for CD (SES-CD) [median (95%CI)]\t12 (11 – 18)\t12 (4 – 25)\tns\t\nIleal SES-CD [median (95%CI)]\t6 (4 – 7)\t6 (3 – 6)\tns\t\nColonic SES-CD [median (95%CI)]\t9 (6 – 12)\t12 (11 – 18)\tns\t\nDisease location – n (%)\t \t \t \t\nL1 (ileal)\t18/44 (41%)\t9/17 (53%)\tns\t\nL3 (ileocolonic)\t26/44 (59%)\t8/17 (47%)\tns\t\nDisease behavior – n (%)\t \t \t \t\nB1 (inflammatory)\t27/44 (61%)\t5/17 (29%)\t0.04\t\nB2 (stricturing)\t6/44 (14%)\t4/17 (24%)\tns\t\nB3 (penetrating)\t11/44 (25%)\t8/17 (47%)\tns\t\nPrevious surgery – n (%)\t15/44 (34%)\t9/17 (53%)\tns\t\nMedications\t \t \t \t\nSteroids\t21/44 (48%)\t5/17 (29%)\tns\t\nAzathioprine\t39/44 (87%)\t14/17 (82%)\tns\t\nAminosalicylates\t43/44 (98%)\t17/17 (100%)\tns\t\nProbiotics\t33/44 (75%)\t13/17 (76%)\tns\t\nAntibiotics\t8/44 (18%)\t7/17 (41%)\tns\t\nPrevious anti-TNF therapy\t5/44 (11%)\t3/17 (18%)\tns\t\nData are presented as means with standard deviations (SD) or medians with 95% confidence intervals (CI).\n\nTable 3 Binary logistic regression analysis showing which features of Crohn’s disease activity assessed in magnetic resonance enterography at week 0 were associated with a secondary non-response in patients treated with anti-TNF antibodies. Data are presented as odds ratios (OR) with 95% confidence intervals (CI).\nFeature\tStatistical significance in predicting secondary non-response to anti-TNF therapy\tThe percentage overall correct classifications\t\nBowel wall thickening\t1 point: OR 0.6; 95% CI (0.2 – 1.7); ns\t—\t\n \t2 points: OR 0.1; 95% CI (0.001 – 10); ns\t \t\nContrast enhancement\t1 point: OR 1.1; 95% CI (0.4 – 25); ns\t—\t\n \t2 points: OR 1.1; 95% CI (0.04 – 33.3); ns\t \t\nFat wrapping\tOR 0.9; 95% CI (0.3 – 2.5); ns\t—\t\nProliferation of mesenteric vasculature\t1 point: OR 1.2; 95% CI (0.6 – 2.5); ns\t—\t\n \t2 points: OR 1.6; 95% CI (0.1 – 25); ns\t \t\nLymphadenopathy\t1 point: OR 1.1; 95% CI (0.5 – 2); ns\t—\t\n \t2 points: OR 1.2; 95% CI (0.07 – 20); ns\t \t\nBowel wall ulcerations\tAnalysis impossible due to too few cases of ulcerations (4 cases, all in the long-term responders group) in analyzed sample\t—\t\nStenosis\t1 point: OR 2.4; 95% CI (1.2 - 5); p = 0.01\t75.40%\t\n \t2 points: OR 5.8; 95% CI (1.4 – 25); p = 0.01\t \t\nIntra-abdominal fistulas\tOR 1.4; 95% CI (1.1 – 2); p = 0.004\t75,5%\t\nDisease extent\t1 point: OR 0.6; 95% CI (0.3 – 1.25); ns\t—\t\n \t2 points: OR 0.4; 95% CI (0.08 – 1.6); ns\t \t\nTable 4 Sequences used in the magnetic resonance enterography protocol.\n \tRepetition time/echo time (ms)\tFlip angle\tSlice thickness (mm)\tIn plane resolution (mm)\tDistance factor (Axial) (mm)\tDistance factor (Coronal)(mm)\t\nTrue Fast Imaging with Steady-state free Precession (FISP)\t4/1,72\t60°\t4,0\t2,0 × 1,5\t0\t0,4\t\nSingle shot turbo spin echo sequence with fat suppression (HASTE)\t1100/116\t150°\t6,0\t1,5 × 1,6\t—\t1,8\t\nRetro Steady State Free Precession\t42,6/1,2\t73°\t6,0\t1,5 × 2\t—\t6,0\t\nFat-suppressed 3D T1-weighted Volumetric Interpolated Breath-Hold Examination (VIBE) before and three times - 30, 90 seconds and 5 minutes after intravenous injection of gadolinium contrast (Gadovist 1.0, Bayer Pharma AG, Germany, dose of 0.1 mmol/kg body weight followed by 20 ml of saline)\t6,10/2,74\t10°\t1,75\t2 × 2\t0,6\t0,6\t\nTable 5 Quantifying score of magnetic resonance enterographic features of Crohn’s disease activity 10.\nMRE feature\tGrading scale\t\nBowel wall thickening\t<3 mm: 0 pts\t3 – 7 mm: 1 pt\t>7 mm: 2 pts\t\nContrast enhancement1\tNone: 0 pts\tHomogenous pattern: 1 pt\tLayered pattern: 2 pts\t\nFat wrapping\tNone: 0 pts\tPresent: 1 pt\t\nProliferation of mesenteric vasculature\tNone: 0 pts\t<5 vessels/3 cm2 of mesenteric fat: 1 pt\t≥ 5 vessels/3 cm2 of mesenteric fat: 2 pts\t\nMesenteric lymphadenopathy\tNone: 0 pts\t<10 enlarged (diameter > 5 mm) lymph nodes: 1 pt\t≥ 10 enlarged (diameter > 5 mm) lymph nodes: 2 pts\t\nBowel wall ulcerations\tNone: 0 pts\tAt least one ulceration present, not exceeding ½ of bowel thickness: 1 pt\tAt least one ulceration present, exceeding ½ of bowel thickness: 2 pts\t\nStenotic complications2\tNone: 0 pts\tStenosis without prestenotic dilatation: 1 pt\tAt least one stenosis with prestenotic dilatation: 2 pts\t\nIntra-abdominal fistulas\tNone: 0 pts\tAt least one intra-abdominal fistula tract visible: 2 pts\t\nExtent of the disease in jejunum or ileum\t<1500 mm: 1 pt\t \t>1500 mm: 2 pts\t\n1assessed in comparison with the adjacent bowel loops.\n\n2decrease in bowel caliber in comparison with the adjacent bowel loops, with dilatation of the proximal segment and/or a collapse of the distal segment.\n==== Refs\nFeagan B. 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Wewn. \n7-8 , 378 –385 (2013 ).23778300 \nTielbeek J. A. \net al.\nSerial magnetic resonance imaging for monitoring medical therapy effects in Crohn’s disease . Inflamm. Bowel Dis. \n19 , 1943 –1950 (2013 ).23765176 \nVan Assche G. \net al.\nEffects of infliximab therapy on transmural lesions as assessed by magnetic resonance enteroclysis in patients with ileal Crohn’s disease . J. Crohns Colitis \n12 , 950 –957 (2013 ).23411006 \nOrdas I. \net al.\nAccuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn’s disease . Gastroenterology \n146 , 374 –382 (2014 ).24177375 \nColombel J. F. \net al.\nAdalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial . Gastroenterology \n132 , 62 –65 (2007 ).\nDretzke J. \net al.\nA systematic review and economic evaluation of the use of tumour necrosis factor alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn’s disease . Health Technol. Assess \n6 , 1 –244 (2011 ).21291629 \nReinisch W. , Wang Y. , Oddens B. J. & Link R. \nC-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn’s disease: a post-hoc analysis from ACCENT I . Aliment. Pharmacol. Ther. \n5 , 568 –576 (2012 ).22251435 \nRubin D. T. , Uluscu O. & Sederman R. \nResponse to biologic therapy in Crohn’s disease is improved with early treatment: an analysis of health claims data . Inflamm. Bowel Dis. \n12 , 2225 –2231 (2012 ).22359399 \nArnott I. D. , McNeill G. & Satsangi J. \nAn analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn’s disease . Aliment. Pharmacol. Ther. \n17 , 1451 –1457 (2003 ).12823146 \nEsters N. \net al.\nSerological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn’s disease . Am. J. Gastroenterol. \n97 , 1458 –1462 (2002 ).12094865 \nPrajapati R. , Plant D. & Barton A. \nGenetic and genomic predictors of anti-TNF response . Pharmacogenomics \n11 , 1571 –1585 (2011 ).22044414 \nD’Haens G. R. \net al.\nEndpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn’s disease . Inflamm. Bowel Dis. \n15 , 1599 –1604 (2009 ).19653291 \nPanes J. \net al.\nImaging techniques for assessment of inflammatory bowel disease: Joint ECCO and ESGAR evidence-based consensus guidelines . J. Crohns Colitis \n7 , 556 –585 (2013 ).23583097 \nAmzallag-Bellenger E. \net al.\nEffectiveness of MR enterography for the assessment of small bowel diseases beyond Crohn disease . Radio Graphics \n32 , 1423 –1444 (2012 ).\nOto A. \net al.\nEvaluation of diffusion-weighted MR imaging for detection of bowel inflammation in patients with Crohn’s disease . Acad. Radiol. \n16 , 597 –603 (2009 ).19282206 \nLouis E. \net al.\nA positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with -308 TNF gene polymorphism . Scand. J. Gastroenterol. \n37 , 818 –824 (2002 ).12190096 \nJurgens M. \net al.\nLevels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn’s disease . Clin. Gastroenterol. Hepatol. \n5 , 421 –427 (2011 ).21334460 \nVelayos F. S. , Kahn J. G. , Sandborn W. J. & Feagan B. G. \nA test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab . Clin. Gastroenterol. Hepatol. \n6 , 654 –666 (2013 ).23357488 \nOrdas I. , Feagan B. G. & Sandborn W. J. \nTherapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease . Clin. Gastroenterol. Hepatol. \n10 , 1079 –1087 (2012 ).22813440 \nRieder F. , Zimmermann E. M. , Remzi F. H. & Sandborn W. J. \nCrohn’s disease complicated by strictures: a systematic review . Gut. \n7 , 1072 –1084 (2013 ).23626373 \nSorrentino D. \nRole of biologics and other therapies in stricturing Crohn’s disease: what have we learnt so far? \nDigestion \n1 , 38 –47 (2008 ).18285676 \nSampietro G. M. , Casiraghi S. & Foschi D. \nPerforating Crohn’s disease: conservative and surgical treatment . Dig. Dis. \n2 , 218 –221 (2013 ).24030229 \nKiss L. S. \net al.\nEarly clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn’s disease . Aliment. Pharmacol. Ther. \n8 , 911 –922 (2011 ).21883326 \nHenriksen M. \net al.\nC-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study . Gut. \n11 , 1518 –1523 (2008 ).18566104 \nMagro F. \net al.\nHigh C-reactive protein in Crohn’s disease patients predicts nonresponse to infliximab treatment . J. Crohns Colitis \n8 , 129 –136 (2014 ).23932786 \nCromer W. E. , Mathis J. M. , Granger D. N. , Chaitanya G. V. & Alexander J. S. \nRole of the endothelium in inflammatory bowel diseases . World J. Gastroenterol. \n5 , 578 –593 (2011 ).21350707 \nSandborn W. J. \net al.\nTreating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases . J. Crohns Colitis \n9 , 927 –935 (2014 ).24713173 \nKoh D. M. \net al.\nMR imaging evaluation of the activity of Crohn’s disease . Am. J. Roentgenol. \n177 , 1325 –1332 (2001 ).11717076 \nHorthuis K. , Bipat S. , Stokkers P. C. & Stoker J. \nMagnetic resonance imaging for evaluation of disease activity in Crohn’s disease: a systematic review . Eur. Radiol. \n19 , 1450 –1460 (2009 ).19189109 \nGallego Ojea J. C. , Echarri Piudo A. I & Porta Vila A. \nCrohn’s disease: the usefulness of MR enterography in the detection of recurrence after surgery . Radiologia . 53 , 552 –559 (2011 ).21450324 \nTolan D. J. \net al.\nMR enterographic manifestations of small bowel Crohn’s disease . RadioGraphics \n30 , 367 –384 (2010 ).20228323 \nPunwani S. \net al.\nMural inflammation in Crohn’s disease: location-matched histologic validation of MR imaging features . Radiology \n252 , 712 –720 (2009 ).19635832 \nSchleder S. \net al.\nInterobserver agreement in MR enterography for diagnostic assessment in patients with Crohn’s disease . Rofo. \n184 , 992 –997 (2013 ).23893750 \nBungay H. \nSmall bowel imaging in Crohn’s disease . Frontline Gastroenterol. \n3 , 39 –46 (2012 ).\nBest W. R. , Becktel J. M. , Singelton J. W. & Kern F. Jr.\nDevelopment of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study . Gastroenterology \n70 , 439 –444 (1976 ).1248701 \nDaperno M. \net al.\nDevelopment and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD . Gastrointest. Endosc. \n60 , 505 –12 (2004 ).15472670\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-2322", "issue": "5()", "journal": "Scientific reports", "keywords": null, "medline_ta": "Sci Rep", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D019540:Area Under Curve; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007082:Ileum; D000069285:Infliximab; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012189:Retrospective Studies; D016896:Treatment Outcome", "nlm_unique_id": "101563288", "other_id": null, "pages": "10223", "pmc": null, "pmid": "25993615", "pubdate": "2015-05-20", "publication_types": "D016428:Journal Article", "references": "11717076;12094865;12190096;1248701;12823146;15472670;17241859;18285676;18566104;19189109;19282206;19635832;19653291;20228323;21122530;21180547;21291629;21334460;21350707;21450324;21744431;21883326;22038857;22044414;22072290;22251435;22359399;22813440;22977028;23122965;23293739;23357488;23411006;23474779;23583097;23626373;23765176;23778300;23789658;23893750;23932786;24030229;24177375;24713173;28839630", "title": "Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies.", "title_normalized": "magnetic resonance enterographic predictors of one year outcome in ileal and ileocolonic crohn s disease treated with anti tumor necrosis factor antibodies" }

[ { "companynumb": "PL-JNJFOC-20150902776", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "AT WEEK 0-2-6, TILL WEEK 12", "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROBIOTICS NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROBIOTICS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fistula", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal stenosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EDER P, MICHALAK M, KATULSKA K, LYKOWSKA-SZUBER L, KRELA-KAZMIERCZAK I, STAWCZYK-EDER K, ET AL. MAGNETIC RESONANCE ENTEROGRAPHIC PREDICTORS OF ONE-YEAR OUTCOME IN ILEAL AND ILEOCOLONIC CROHN^S DISEASE TREATED WITH ANTI-TUMOR NECROSIS FACTOR ANTIBODIES. SCIENTIFIC REPORTS 2015;5.", "literaturereference_normalized": "magnetic resonance enterographic predictors of one year outcome in ileal and ileocolonic crohn s disease treated with anti tumor necrosis factor antibodies", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20150909", "receivedate": "20150909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11480415, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Drug-induced liver injury (DILI) is rare in children and adolescents, and, consequently, data are remarkably limited. We analyzed the causes, clinical and biochemical features, natural history, and outcomes of children with DILI. Consecutive children with DILI from 1997 to 2004 (retrospective) and 2005 to 2010 (prospective) were studied based on standard criteria for DILI. Thirty-nine children constituted 8.7% of 450 cases of DILI. There were 22 boys and 17 girls. Median age was 16 years (range, 2.6-17). Combination antituberculous drugs were the most common cause (n = 22), followed by the anticonvulsants, phenytoin (n = 10) and carbamazepine (n = 6). All of the 16 children (41%) who developed hypersensitivity features, such as skin rashes, fever, lymphadenopathy, and/or eosinophilia, including the 3 with Stevens-Johnson syndrome, survived. Those with hypersensitivity presented earlier (24.5 versus 35 days; P = 0.24) had less severe disease (MELD, 16 versus 29; P = 0.01) and had no mortality (0/16 versus 12/23; P < 0.001), compared to those without hypersensitivity. The 12 fatalities were largely the result of antituberculous DILI (n = 11). The presence of encephalopathy and ascites were associated with mortality, along with hyperbilirubinemia, high international normalized ratio, and serum creatinine. According to the Roussel Uclaf Causality Assessment Method, 18 were highly probable, 14 probable, and 7 possible. Thirty-two children were hospitalized.\n\n\nCONCLUSIONS\nDILI is not uncommon in children and accounts for 8.7% of all patients with DILI. Antituberculous drugs and anticonvulsants are the leading causes of DILI in India. Overall mortality is high (30.7%), largely accounted by antituberculous drugs. Children with DILI and hypersensitivity features present early, have less severe disease, and, consequently, a better prognosis, compared to those without, and are often associated with anticonvulsants or sulfonamides.", "affiliations": "Department of Gastroenterology, St. John's Medical College Hospital, Bangalore, India. [email protected]", "authors": "Devarbhavi|Harshad|H|;Karanth|Dheeraj|D|;Prasanna|K S|KS|;Adarsh|C K|CK|;Patil|Mallikarjun|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/hep.24527", "fulltext": null, "fulltext_license": null, "issn_linking": "0270-9139", "issue": "54(4)", "journal": "Hepatology (Baltimore, Md.)", "keywords": null, "medline_ta": "Hepatology", "mesh_terms": "D000293:Adolescent; D017677:Age Distribution; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D004342:Drug Hypersensitivity; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D015994:Incidence; D007194:India; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D018709:Statistics, Nonparametric; D015996:Survival Rate", "nlm_unique_id": "8302946", "other_id": null, "pages": "1344-50", "pmc": null, "pmid": "21735470", "pubdate": "2011-10", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Drug-Induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents.", "title_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents" }

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DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151109", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701224, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000663", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706427, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000662", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706616, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362035", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701216, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362032", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000664", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151109", "receivedate": "20151109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11715160, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362033", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54 (4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701225, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362030", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54:1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701241, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-PFIZER INC-2015362027", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008762", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI, H.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS. HEPATOLOGY. 2011?54:1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151105", "receivedate": "20151105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11701221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000660", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706431, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2015VAL000661", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021710", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVARBHAVI H, KARANTH D, PRASANNA KS, ADARSH CK, PATIL M.. DRUG INDUCED LIVER INJURY WITH HYPERSENSITIVITY FEATURES HAS A BETTER OUTCOME: A SINGLE CENTER EXPERIENCE OF 39 CHILDREN AND ADOLESCENTS.. HEPATOLOGY. 2011?54(4):1344-1350", "literaturereference_normalized": "drug induced liver injury with hypersensitivity features has a better outcome a single center experience of 39 children and adolescents", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151106", "receivedate": "20151106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11706441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "BACKGROUND\nPoisoning is a worldwide public health problem that involves individuals of all ages and a wide range of chemicals. This study investigated the data from two health information systems to characterize poisoning events in the Federal District (DF), Brazil.\n\n\nMETHODS\nData related to the period from 2009 to 2013 were obtained from the poison information center (Centro de Informação Toxicológica, CIT) and the Notifiable Diseases Information System (Sistema Nacional de Agravos de Notificação, SINAN) of the DF.\n\n\nRESULTS\nA total of 3622 cases were reported to CIT-DF and 5702 cases to SINAN-DF. Most of the cases in CIT-DF (53%) occurred with children up to 9 years old, while this corresponded to 33.9% in SINAN-DF. Unintentional poisoning was the main circumstance involved in the cases. Pharmaceuticals were the main agent (44.3-47.1% of the cases), mainly clonazepan and paracetamol, and pesticides the most fatal (2.4% fatality rate). Out of the 47 fatal cases reported to the systems, only four were reported to both; six cases occurred with children up to 6 years.\n\n\nCONCLUSIONS\nUnder-reporting and missing information were identified in both systems, but the data were complementary to describe the epidemiology of poisoning cases in the DF.", "affiliations": "Poison Information Center of the Federal District, Heath Department of the Government of Federal District, Brasilia, DF, Brazil.;Laboratory of Toxicology, Department of Pharmaceutical Sciences, University of Brasilia, Brasilia, DF, Brazil.", "authors": "Magalhães|Andrea Franco Amoras|AFA|;Caldas|Eloisa Dutra|ED|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/pubmed/fdy008", "fulltext": null, "fulltext_license": null, "issn_linking": "1741-3842", "issue": "41(1)", "journal": "Journal of public health (Oxford, England)", "keywords": "Brazil; Federal District; chumbinho; information systems; pesticides; pharmaceuticals; poisoning", "medline_ta": "J Public Health (Oxf)", "mesh_terms": "D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D003625:Data Collection; D005260:Female; D063005:Health Information Systems; D006801:Humans; D007223:Infant; D008297:Male; D019221:Mandatory Reporting; D008875:Middle Aged; D011039:Poison Control Centers; D011041:Poisoning; D011247:Pregnancy; D012189:Retrospective Studies; D035141:Voluntary Programs; D055815:Young Adult", "nlm_unique_id": "101188638", "other_id": null, "pages": "203-211", "pmc": null, "pmid": "29509912", "pubdate": "2019-03-01", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Two health information systems to characterize poisoning in Brazil-a descriptive study.", "title_normalized": "two health information systems to characterize poisoning in brazil a descriptive study" }

[ { "companynumb": "BR-PFIZER INC-2019164894", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "050670", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." } ], "patientagegroup": null, "patientonsetage": "1", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Accidental exposure to product", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MAGALHAES, A.. TWO HEALTH INFORMATION SYSTEMS TO CHARACTERIZE POISONING IN BRAZIL- A DESCRIPTIVE STUDY. JOURNAL OF PUBLIC HEALTH. 2019?41(1):203-211", "literaturereference_normalized": "two health information systems to characterize poisoning in brazil a descriptive study", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20190422", "receivedate": "20190422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16224210, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "BR-JNJFOC-20200715007", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product prescribing error", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAGALHAES A, CALDAS E. TWO HEALTH INFORMATION SYSTEMS TO CHARACTERIZE POISONING IN BRAZIL A DESCRIPTIVE STUDY. JOURNAL OF PUBLIC HEALTH. 2018 MAR 02?41 (1):203?211.", "literaturereference_normalized": "two health information systems to characterize poisoning in brazil a descriptive study", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20200716", "receivedate": "20200716", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18032850, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "We studied the outcome of 47 adult patients with relapsed acute leukaemia (AML = 25 and ALL = 22) treated with FLAG-mitoxantrone regimen. Median time to relapse was 10.7 months (range 1.9-27.7). Complete remission (CR2) was 60.1% which was significantly more frequent in ALL compared to AML (P = 0.049). WBC count < 100 × 109/L at initial diagnosis and time to relapse > 1 year were significantly predictor for CR2 in AML (P = 0.005 for both). Induction death was significantly higher in ALL compared to AML (P = 0.039). Median follow-up was 4.0 months (0.9-119.8) for AML and 2.1 months (range 0.6-118.1) for ALL. Nine patients underwent allogeneic stem-cell transplantation (allo-SCT). Estimated overall survival (OS) at 12 and 18 months was 60.5 and 34.6%, respectively, for AML, and 39.9 and 29.9%, respectively, for ALL. For AML patients failure to achieve CR, WBC count at initial diagnosis > 5 × 109/L and poor cytogenetic risk group was significant predictors of poor OS (P = 0.010, P = 0.025, and P = 0.015, respectively). For ALL patients failure to achieve of CR, WBC count at relapse < 5 × 109/L (CR patients) and lack of any type of consolidation therapy were significant predictor of poor OS (P < 0.001, P = 0.008, P = 0.008, respectively).", "affiliations": "Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. [email protected].;Mediclinic North Wing, Dubai, United Arab Emirates.;Department of Hematology, Oncology Tawam Hospital, Al Ain, United Arab Emirates.;Department of Hematology, Oncology Tawam Hospital, Al Ain, United Arab Emirates.", "authors": "Hassan|Inaam Bashir|IB|;Kristensen|Jorgen|J|;Al Qawasmeh|Khalid|K|;Alam|Arif|A|", "chemical_list": "D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D008942:Mitoxantrone; D014740:Vidarabine", "country": "Japan", "delete": false, "doi": "10.1007/s12185-018-2478-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "108(4)", "journal": "International journal of hematology", "keywords": "ALL; AML; FLAG–mitoxantrone; Re-induction; Relapse", "medline_ta": "Int J Hematol", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D018572:Disease-Free Survival; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D060828:Induction Chemotherapy; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D012008:Recurrence; D015996:Survival Rate; D014479:United Arab Emirates; D014740:Vidarabine", "nlm_unique_id": "9111627", "other_id": null, "pages": "390-401", "pmc": null, "pmid": "29951735", "pubdate": "2018-10", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": "7528855;9815970;2045861;19806665;14675405;15856358;3276823;17611565;1737098;19543516;23407597;9722289;16832677;25922062;20872554;18076637;11475146;15632409;11806988;14671635;19880497;11574763;27587380;20714942;16988532;20385793;8374873;20003823;17032921;23468219;11167793;27207612;19008455;23243288;10738999;21131038;16105981;8418222;20010621;22511497", "title": "Re-induction chemotherapy using FLAG-mitoxantrone for adult patients with relapsed acute leukemia: a single-center experience from United Arab Emirates.", "title_normalized": "re induction chemotherapy using flag mitoxantrone for adult patients with relapsed acute leukemia a single center experience from united arab emirates" }

[ { "companynumb": "PHHY2018AE121284", "fulfillexpeditecriteria": "1", "occurcountry": "AE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G/M2, UNK(OVER 2 H, DAYS 1-5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/M2, UNK(1 H AT DAYS 1, 3, AND 5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "125553", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 UG, QD (FROM DAY 6 )", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/M2, UNK (OVER 30 MIN, DAYS 1-5)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute leukaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Recurrent cancer", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HASSAN IB, KRISTENSEN J, QAWASMEH KA, ALAM A. RE-INDUCTION CHEMOTHERAPY USING FLAG-MITOXANTRONE FOR ADULT PATIENTS WITH RELAPSED ACUTE LEUKEMIA: A SINGLE-CENTER EXPERIENCE FROM UNITED ARAB EMIRATES.. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2018?108(4):391-401", "literaturereference_normalized": "re induction chemotherapy using flag mitoxantrone for adult patients with relapsed acute leukemia a single center experience from united arab emirates", "qualification": "3", "reportercountry": "AE" }, "primarysourcecountry": "AE", "receiptdate": "20181012", "receivedate": "20181012", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15494593, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "The purpose of this study was to evaluate the incidence of the administration of potentially inappropriate medications (PIMs) and the potential drug-drug interactions (pDDIs) in older patients in emergency departments (EDs) over a 12-month period and to identify the factors associated with the administration of PIMs.\nThis retrospective study was conducted using the electronic medical records from two university-affiliated teaching hospitals in South Korea. ED visit cases of patients aged 65 and older from January 1, 2013, to December 31, 2013, were included in the analysis. Among the medications administered in ED, PIMs or pDDIs were identiﬁed using a drug utilization review program available in Korea.\nDuring the study period, a total of 13,002 ED visit cases were reported from 10,686 patients. The proportion of ED visit cases with any PIM was 79.2% and the average number of PIMs was 2.7 (range, 1-17). The most commonly administered PIMs that were contraindicated or should have been used with caution were ketorolac (41.3%) and metoclopramide (10.3%), respectively. Multivariate regression analysis indicated that female patients (p = 0.012), patients with more than six drugs in the ED (p < 0.001), and visits longer than 300 minutes (p = 0.026) were significantly associated with PIM administration in the ED. Potential DDIs between the medications administered in EDs were observed in 20.5% of total visit cases, with ketorolac being the most frequently reported drug in contraindicated drug combinations.\nThis study demonstrated a high incidence of the administration of PIMs and medications with pDDIs in older patients in EDs and revealed the characteristics that are significantly associated with an increased risk of PIM administration. Healthcare providers in EDs should consider the risk of administering PIMs or medications with pDDIs, especially when treating older patients.", "affiliations": "College of Pharmacy, Korea University, Sejong, Republic of Korea.;Institute of Pharmaceutical Science, Korea University, Sejong, Republic of Korea.;Department of Pharmacy, Gang Neung Asan Hospital, Gangneung, Republic of Korea.;Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.;College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.;College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea.", "authors": "Kim|Kyungim|K|0000-0001-7997-696X;Jung|Jinyoung|J|0000-0002-6038-6860;Kim|Haesook|H|;Kim|Jung Tae|JT|;Oh|Jung Mi|JM|0000-0002-1836-1707;Kim|Hyunah|H|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/TCRM.S291458", "fulltext": "\n==== Front\nTher Clin Risk Manag\nTher Clin Risk Manag\ntcrm\ntcriskman\nTherapeutics and Clinical Risk Management\n1176-6336 1178-203X Dove \n\n291458\n10.2147/TCRM.S291458\nOriginal Research\nPotentially Inappropriate Prescriptions to Older Patients in Emergency Departments in South Korea: A Retrospective Study\nKim et alKim et alhttp://orcid.org/0000-0001-7997-696XKim Kyungim 12* http://orcid.org/0000-0002-6038-6860Jung Jinyoung 2* Kim Haesook 3 Kim Jung Tae 4 http://orcid.org/0000-0002-1836-1707Oh Jung Mi 5 Kim Hyunah 67 1 College of Pharmacy, Korea University, Sejong, Republic of Korea\n2 Institute of Pharmaceutical Science, Korea University, Sejong, Republic of Korea\n3 Department of Pharmacy, Gang Neung Asan Hospital, Gangneung, Republic of Korea\n4 Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea\n5 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea\n6 College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea\n7 Drug Information Research Institute, College of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea\nCorrespondence: Hyunah Kim College of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul,04310, Republic of KoreaTel +82-2-2077-7961 Email [email protected]* These authors contributed equally to this work\n\n\n19 2 2021 \n2021 \n17 173 181\n10 11 2020 18 1 2021 © 2021 Kim et al.2021Kim et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nThe purpose of this study was to evaluate the incidence of the administration of potentially inappropriate medications (PIMs) and the potential drug–drug interactions (pDDIs) in older patients in emergency departments (EDs) over a 12-month period and to identify the factors associated with the administration of PIMs.\n\nPatients and Methods\nThis retrospective study was conducted using the electronic medical records from two university-affiliated teaching hospitals in South Korea. ED visit cases of patients aged 65 and older from January 1, 2013, to December 31, 2013, were included in the analysis. Among the medications administered in ED, PIMs or pDDIs were identiﬁed using a drug utilization review program available in Korea.\n\nResults\nDuring the study period, a total of 13,002 ED visit cases were reported from 10,686 patients. The proportion of ED visit cases with any PIM was 79.2% and the average number of PIMs was 2.7 (range, 1–17). The most commonly administered PIMs that were contraindicated or should have been used with caution were ketorolac (41.3%) and metoclopramide (10.3%), respectively. Multivariate regression analysis indicated that female patients (p = 0.012), patients with more than six drugs in the ED (p < 0.001), and visits longer than 300 minutes (p = 0.026) were significantly associated with PIM administration in the ED. Potential DDIs between the medications administered in EDs were observed in 20.5% of total visit cases, with ketorolac being the most frequently reported drug in contraindicated drug combinations.\n\nConclusion\nThis study demonstrated a high incidence of the administration of PIMs and medications with pDDIs in older patients in EDs and revealed the characteristics that are significantly associated with an increased risk of PIM administration. Healthcare providers in EDs should consider the risk of administering PIMs or medications with pDDIs, especially when treating older patients.\n\nKeywords\nemergency departmentolder adultspotentially inappropriate medicationsdrug–drug interactionsdrug utilization reviewNational Research Foundation, KoreaMinistry of Health & WelfareThis study was supported by the National Research Foundation, Korea (NRF-2020R1F1A1069257) and the Ministry of Health & Welfare (MOHW, Korea).\n==== Body\nIntroduction\nThe emergency department (ED), the place to institute the immediate medical care of patients with acute illness or injury, is at the intersection between inpatient and outpatient care and can have a meaningful impact on patients’ conditions.1–3 However, EDs are of increasing concern as high-risk environments for potentially inappropriate medication (PIM) use and adverse drug events. Certain characteristics of EDs such as patients overcrowding, a lack of skilled workers, and the high turnover of admitted or discharged patients can hinder the provision of optimal emergency care services.4,5\n\nAs the aging of society accelerates, the older adults aged 65 and over account for the largest and fastest growing age group of patients visiting EDs. The proportion of visits by older patients to EDs was reported as 24% in Italy, 31% in Spain, and 22% in the United States.6–8 In Korea, the rate of admission to EDs by older patients has risen from 15.2% in 2005 to 23.9% in 2016.9 Because older adults are sensitive to medicines, the administration of PIMs can lead to adverse drug events, which can have serious medical and safety consequences especially for older adults.10 Moreover, the side effects of these drugs can cause problems long after administration, as many drugs have a longer half-life in the older adults than in younger age people due to changes in pharmacokinetic parameters with aging.11 Some previous studies have shown that exposure to PIMs or potential drug–drug interactions (pDDIs) was associated with an increased risk of re-hospitalization and unplanned hospitalization in the older adults.12–14 Therefore, the need for and importance of appropriate medication use for the older adults visiting EDs should be particularly emphasized.\n\nPotentially inappropriate prescriptions have been well studied in both nursing home and community-dwelling older adult settings. However, less is known about it for older patients visiting EDs. Therefore, the purposes of this study were to determine the incidence and characteristics of PIM use and pDDIs and to identify the factors related to PIM administration, with a particular focus on the older patients visiting EDs.\n\nPatients and Methods\nStudy Population and Data Collection\nThis retrospective study was conducted from January to December 2013 at two university-affiliated teaching hospitals in South Korea. Of the patients who visited the EDs in 2013, those aged 65 years and older were included in this study. Patient demographic information and visit characteristics to the EDs were collected from each hospital’s electronic medical records (EMRs). These included the patient’s age, sex, diagnosis in the ED (ICD-10 code), the medications administered in the ED (brand name, ingredient, ATC code), their length of ED stay, and condition after discharge from the ED. Information about the medications that were administered in the ED was prepared by checking the actual dosing time on the EMR, not simply the physician’s order list. To protect the privacy of the patients involved, all data were encoded and protected. This study was conducted with the approval of the Institutional Review Board of Kyung Hee University Hospital at Gangdong (IRB No. 2014-08-003) and Gangneung Asan Hospital (IRB No. 2014–046) in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.\n\nEvaluation of PIMs and pDDIs\nPotentially inappropriate medications and pDDIs in the older adults were identiﬁed using a commercially available drug utilization review (DUR) database program in Korea (DIKPlus, FirstDIS Ltd, Seoul, Korea). This DUR program provides information on drug–drug interactions, contraindications, and precautions for special population groups such as older adults, children, as well as pregnant and breastfeeding women. For PIMs and pDDIs in older adults, the database was developed by reviewing the Beers Criteria of the American Geriatric Society and the list of drugs to be used with caution in older patients which is provided by the Korea Food and Drug Administration. In addition, product package inserts, US Hospital Preparation Service (AHFS) medication information, Merck manual, US Food and Drug Administration MedWatch and Health Canada were reviewed. Based on these databases, this DUR program classified PIMs in older patients into two groups according to their severity: contraindications (severity level II) and precautions (severity level I). Potential DDIs were classified into three groups: contraindications (severity level III), severe interactions requiring treatment modification (severity level II), and moderate interactions requiring careful monitoring (severity level I).\n\nIn this study, medications that are inappropriate only at a specific dose, duration of administration, or comorbid conditions were not included because this information could not be identified. Therefore, the PIMs and pDDIs considered in this study were those listed on the references regardless of diagnosis or condition.\n\nStatistical Analysis\nAll the statistical analysis was performed on an ED visit, rather than patient case basis. Categorical variables were summarized as values and percentages, and continuous variables were presented as medians and ranges. To understand the characteristics of the medications administered in ED, a descriptive analysis was performed. Multivariate logistic regression analysis was used to identify the predictors of PIM administration. For each ED visit case, the independent variables in the regression model included patient characteristics, such as sex and age, and visit characteristics, such as the number of medications administered and the length of stay. The dependent variable was the PIM occurrence. Two-sided P-values less than 0.05 were considered as statistically significant. All analyses were performed using SAS.\n\nResults\nCharacteristics of the ED Visit Cases\nTable 1 shows the overall characteristics of the ED visit cases. During the study period, a total of 13,002 ED visit cases by 10,686 patients were reported. Some patients had visited the ED more than once (range, 1–18). The median age for the ED visit cases was 74 years (range, 65–104 years). Out of the total cases, 6094 (46.9%) were male and 6908 (53.1%) were female. The median number of diagnoses and medications administered in EDs was 1 (range, 1–3) and 5 (range, 1–55), respectively. The five most common diseases diagnosed in EDs were “Cerebral infarction, unspecified” (545, 4.2%), “Dizziness and giddiness” (463, 3.6%), “Gastroenteritis and colitis of unspecified origin” (336, 2.6%), “Pneumonia, unspecified” (318, 2.5%) and “Unspecified abdominal pain” (204, 1.6%) (Supplementary Table S1). The average length of ED stay was 196 minutes (range, 1–2208 minutes). After the ED visit, there were 6698 cases of hospitalizations (51.5%) and 6154 cases of discharge (47.4%).\nTable 1 Characteristics of the ED Visit Cases\n\nCharacteristics, No. (%)\tTotal Visit\tVisit with PIMsa\tVisit without PIMa\tP-value\t\nNo. of visits\t13,002 (100.0)\t10,291 (79.1)\t2711 (20.9)\t-\t\nSex\t\nMale\t6094 (46.9)\t4776 (46.4)\t1318 (48.6)\t0.040\t\nFemale\t6908 (53.1)\t5515 (53.6)\t1393 (51.4)\t\t\nAge (year)\t\n65–74\t6569 (50.5)\t5274 (51.2)\t1295 (47.8)\t0.005\t\n75–84\t4891 (37.6)\t3816 (37.1)\t1075 (39.7)\t\n≥ 85\t1542 (11.9)\t1201 (11.7)\t341 (12.6)\t\t\nNo. of diagnoses in ED\t\n1\t12,484 (96.0)\t9888 (96.1)\t2596 (95.8)\t0.440\t\n≥ 2\t518 (4.0)\t403 (3.9)\t115 (4.2)\t\t\nNo. of medications administered in ED\t\n1–5\t7827 (60.2)\t5222 (50.7)\t2605 (96.1)\t< 0.001\t\n6–7\t2324 (17.9)\t2256 (21.9)\t68 (2.5)\t\n≥ 8\t2851 (21.9)\t2813 (27.3)\t38 (1.4)\t\t\nLength of ED stay (minutes)\t\n1–196\t6533 (50.2)\t5065 (49.2)\t1468 (54.1)\t< 0.001\t\n197–299\t3235 (24.9)\t2528 (24.6)\t707 (26.1)\t\n≥ 300\t3234 (24.9)\t2698 (26.2)\t536 (19.8)\t\t\nCondition after ED visit\t\nHospitalization\t6698 (51.5)\t5439 (52.9)\t1259 (46.4)\t< 0.001\t\nHome\t6154 (47.4)\t4714 (45.8)\t1440 (53.1)\t\nDeath\t121 (0.9)\t116 (1.1)\t5 (0.2)\t\nNot assessed\t29 (0.2)\t22 (0.2)\t7 (0.3)\t\nNote:\naEach percentage was calculated out of the total number of corresponding visits.\n\nAbbreviations: ED, emergency department; PIM, potentially inappropriate medication.\n\n\n\n\nAnalysis of PIM Use\nOf the total ED visit cases, 10,291 (79.2%) contained at least one PIM in their ED administered medication. Between the visit cases with PIMs and those without them, there were significant differences in sex, age, number of medications administered, length of ED stay, and post-discharge status (Table 1).\n\nOf the visit cases with at least one PIM, the average number of PIMs administered in ED was 2.7 (range, 1–17). A total of 7355 (71.5%) visits received ≥2 PIMs, and 4584 (44.5%) visits received ≥3 PIMs. There were 303 (2.9%) visit cases with only PIMs of severity II (contraindications) and 8125 (79.0%) visit cases with only PIMs of severity I (precautions). Moreover, 1863 (18.1%) visit cases had PIMs of both severities I and II (Table 2).\nTable 2 Incidence of Visit Cases with PIM\n\nSeverity Level\tNo. of Visit with PIMs (%)\tNo. of PIMs Administered, Average (Range)\t\nII only\t303 (2.9)\t1.2 (1–4)\t\nI only\t8125 (79.0)\t2.5 (1–16)\t\nII and I\t1863 (18.1)\t4.2 (2–17)\t\nAbbreviation: PIM, potentially inappropriate medication.\n\n\n\n\nIn this study, 22 and 219 PIMs corresponding to severity II and I were administered 2615 and 25,343 times, respectively. The five most commonly administered medications are listed in Table 3. The administered PIMs corresponding to severity II in order of the most common were ketorolac (1081, 41.3%), chlorpheniramine (615, 23.5%), midazolam (236, 9.0%), diazepam (197, 7.5%), and triprolidine/pseudoephedrine (114, 4.4%). These five medications accounted for 85.8% of all the severity level II PIMs. Other medications, including methocarbamol, nifedipine (short-acting), amitriptyline, bisacodyl, and piroxicam accounted for a smaller percentage of the total PIMs (Supplementary Table S2). When analyzed in the same way, the administered PIMs corresponding to severity level I in order of the most common were metoclopramide (2606, 10.3%), famotidine (2312, 9.1%), tramadol (1822, 7.2%), acetaminophen (1269, 5.0%) and nitroglycerine (981, 3.9%). These five medications accounted for 35.5% of all the severity level I PIMs. Other medications such as aspirin, heparin, ranitidine, furosemide, fluoroquinolones (ciprofloxacin, levofloxacin), and opioids (pethidine, fentanyl, morphine) followed (Supplementary Table S3).\nTable 3 Top 5 Ranked PIMs\n\nSeverity Level\tMedication\tn (%)a\t\nSeverity II: Contraindications\tKetorolac\t1081 (41.3)\t\nChlorpheniramine\t615 (23.5)\t\nMidazolam\t236 (9.0)\t\nDiazepam\t197 (7.5)\t\n\tTriprolidine/pseudoephedrine\t114 (4.4)\t\nSeverity I: Precautions\tMetoclopramide\t2606 (10.3)\t\nFamotidine\t2312 (9.1)\t\nTramadol\t1822 (7.2)\t\nAcetaminophen\t1269 (5.0)\t\nNitroglycerine\t981 (3.9)\t\nNote:\naEach percentage was calculated out of the total number of administration at each severity level.\n\nAbbreviation: PIM, potentially inappropriate medication.\n\n\n\n\nThe results of the multivariate logistic regression analysis are noted in Table 4. They indicated that female patients were more associated with increased risk of PIM administration than male patients, and this difference was significant [OR 1.13 (1.03–1.23), p = 0.012]. The visits associated with administered medications numbering six to seven and eight or more had higher risks of PIM administration when compared to the control [OR 16.42 (12.85–21.00), p < 0.001; OR 36.23 (26.21–50.09), p < 0.001; respectively] (Figure 1). It was found that the length of ED stay of more than 300 minutes had a significantly higher risk of PIM administration than the control [1.15 (1.02–1.29), p = 0.026]. However, those aged between 75 and 84 were significantly associated with a decreasing odds ratio of PIM administration [OR 0.88 (0.79–0.97), p = 0.008].\nTable 4 Crude and Adjusted Odds Ratios for Factors Influencing PIM Administration\n\nCharacteristics\tCrude Model\tAdjusted Model\t\nOR (95% CI)\tP-value\tOR (95% CI)\tP-value\t\nSex\t\nMale\t1.00 (Reference)\t\t1.00 (Reference)\t\t\nFemale\t1.09 (1.004–1.19)\t0.041\t1.13 (1.03–1.23)\t0.012\t\nAge (years)\t\n65–74\t1.00 (Reference)\t\t1.00 (Reference)\t\t\n75–84\t0.87 (0.80–0.96)\t0.003\t0.88 (0.79–0.97)\t0.008\t\n≥ 85\t0.87 (0.76–0.99)\t0.035\t0.87 (0.75–1.002)\t0.053\t\np-for trend\t\t0.004\t\t0.007\t\nNo. of medications administered in ED\t\n1–5\t1.00 (Reference)\t\t1.00 (Reference)\t\t\n6–7\t16.55 (12.94–21.16)\t< 0.001\t16.42 (12.85–21.00)\t< 0.001\t\n≥ 8\t36.9 (26.71–50.99)\t< 0.001\t36.23 (26.21–50.09)\t< 0.001\t\np-for trend\t\t< 0.001\t\t< 0.001\t\nLength of ED stay (minutes)\t\n1–196\t1.00 (Reference)\t\t1.00 (Reference)\t\t\n197–299\t1.04 (0.94–1.15)\t0.491\t1.01 (0.90–1.12)\t0.903\t\n≥ 300\t1.46 (1.31–1.63)\t< 0.001\t1.15 (1.02–1.29)\t0.026\t\np-for trend\t\t< 0.001\t\t0.029\t\nAbbreviations: ED, emergency department; PIM, potentially inappropriate medication.\n\n\nFigure 1 Relationship between PIM incidence and the number of medications administered in ED.\n\nAbbreviations: PIM, potentially inappropriate medication; ED, emergency department.\n\nAnalysis of pDDIs\nDuring the study period, pDDI between the medications administered in ED was observed in 2668 visit cases (20.5% of the total visit cases). Potential DDIs corresponding to severity III (contraindications), severity II (severe interactions), and severity I (moderate interactions) were reported from 161 visits (1.2%), 607 visits (4.7%), and 1900 visits (14.6%), respectively. The five most commonly administered medication combinations with respect to the three severity levels are listed in Table 5. The medication combinations corresponding to severity III were in the order of the most common ketorolac-aceclofenac (61, 37.9%), ketorolac-celecoxib (32, 19.9%), ketorolac-ibuprofen (20, 12.4%), levofloxacin-amiodarone (12, 7.5%), and esomeprazole-clopidogrel (10, 6.2%). These five combinations accounted for 83.9% of all the severity level III pDDIs (Supplementary Table S4). When analyzed in the same way, the medication combinations corresponding to severity II were in the order of the most common aspirin-heparin (424, 69.9%), levofloxacin-human insulin (31, 5.1%), ciprofloxacin-human insulin (17, 2.8%), amiodarone-diltiazem (13, 2.1%), and amitriptyline-acetaminophen/tramadol (13, 2.1%), and those corresponding to severity I were in the order of the most common aspirin-clopidogrel (510, 26.8%), heparin-clopidogrel (346, 18.2%), atorvastatin-clopidogrel (181, 9.5%), furosemide-candesartan (73, 3.8%), and levofloxacin-budesonide (47, 2.5%) (Supplementary Table S5 and S6).\nTable 5 Top 5 Ranked pDDIs\n\nSeverity Level\tDrug-Drug Interaction\tn (%)a\t\nSeverity III: Contraindications\tKetorolac-aceclofenac\t61 (37.9)\t\nKetorolac-celecoxib\t32 (19.9)\t\nKetorolac-ibuprofen\t20 (12.4)\t\nLevofloxacin-amiodarone\t12 (7.5)\t\n\tEsomeprazole-clopidogrel\t10 (6.2)\t\nSeverity II: Severe interactions\tAspirin-heparin\t424 (69.9)\t\nLevofloxacin-human insulin\t31 (5.1)\t\nCiprofloxacin-human insulin\t17 (2.8)\t\nAmiodarone-diltiazem\t13 (2.1)\t\n\tAmitriptyline-acetaminophen/tramadol\t13 (2.1)\t\nSeverity I: Moderate interactions\tAspirin-clopidogrel,\t510 (26.8)\t\nHeparin-clopidogrel,\t346 (18.2)\t\nAtorvastatin-clopidogrel\t181 (9.5)\t\nFurosemide-candesartan\t73 (3.8)\t\n\tLevofloxacin-budesonide\t47 (2.5)\t\nNote:\naEach percentage was calculated out of the total number of pDDIs at each severity level.\n\nAbbreviation: pDDIs, potential drug–drug interactions.\n\n\n\n\nDiscussion\nTo the best of our knowledge, this is the first DUR study to focus on the appropriateness of the drugs administered in EDs to older Korean patients. There have been a few studies that have evaluated PIMs in older patients in Korea, but all of them were conducted in outpatient settings or long-term care facilities.15–19 This study observed that, of the total ED visit cases by older patients, 79.2% and 20.5% involved at least one PIM and pDDI in the medications administered in ED, respectively. The independent variables of sex, the number of medications administered in ED, and the length of ED stay were significantly associated with PIM administration.\n\nThe overall incidence of PIM administration detected in this study (79.2%) was higher than previous large-scale studies conducted in Western and Asian countries using ED data (15% to 53%).10,20–23 Although Harrison et al reported that 76% of study patients received at least one prescription with PIM according to Beers criteria, the total sample size of their study was small (n = 400).24 The high incidence of the administration of PIMs in this study could be principally explained by the DUR program used in this study, which contains more country-specific medications than the Beers Criteria primarily used in the previous studies. The Beers Criteria has been used to warn of PIM in older patients for a long time, but it is difficult to apply equally to all countries since the available medications and prescription preferences vary by country. In support of this view, Chang et al confirmed that large differences of PIM incidence among older patients in EDs in their study using the Taiwan National Health Insurance Research Database corresponded to differences between country-specific and country non-specific PIM criteria, and they emphasized the importance of establishing country-specific PIM criteria as references for clinical practice in EDs.22\n\nIn this study, the frequently administered PIMs corresponding to severity II (contraindication) were usually symptom relief drugs including ketorolac, chlorpheniramine, benzodiazepines such as midazolam and diazepam, and triprolidine/pseudoephedrine. These results are similar to previous studies.10,21–23 Ketorolac is known to cause gastrointestinal toxicity, and chlorpheniramine may cause sedation and urinary retention due to its anticholinergic activity in the older adults. Benzodiazepines have a sedative effect, and there is a risk of hypotension or paradoxical reactions in the older adults. The current study found that each of the five most frequently administered medications of severity II and I accounted for 85.8% and 35.5% of their total PIMs, respectively. Therefore, it would be very beneficial to encourage ED doctors to consider the risk–benefit ratio before prescribing particularly these drugs, to older patients in ED.\n\nThe multivariate logistic regression analysis in this study identified female patients, the number of medications administered in ED, and the length of ED stay as factors significantly increasing the risk of PIM administration to older patients visiting EDs, and this is consistent with previous studies.10,21 In this regard, previous studies have explained that females are generally more susceptible to inappropriate prescriptions because they are generally at a higher risk of developing several chronic conditions than males.25,26 In addition, female patients are known to use more sleep-inducing drugs, antidepressants, and analgesics than males, because of their higher prevalence of anxiety disorders, depression, and sleep disorders.27 Interestingly, the incidence of PIM administration was reported to be lower in older patients aged between 75 and 84 years than in the control group (aged between 65 and 74). This result could be explained by ED doctors tending to assess the appropriateness of medications more carefully prior to prescribing to older patients. Further research is needed to clarify the reasons for this observation.\n\nPotential DDIs between the medications administered in ED were also evaluated in this study. The pDDI incidence was 20.5% of total visit cases, and the most frequently reported contraindicated drug combinations were ketorolac and other nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac, also the most frequently administered PIM in the current study, can cause serious gastrointestinal problems such as bleeding or peptic ulcers. Its gastrointestinal toxicity is known to be five times stronger than any other NSAID.28 Moreover, ketorolac combinations with other NSAIDs may enhance the risk of gastrointestinal adverse effects.\n\nThe prescriptions given in ED are short-term and one-time doses, and the ED situation is generally more critically urgent than that of any other station. Nevertheless, PIMs or pDDIs should be considered carefully since in older patients they can cause severe adverse effects, even in a single dose. Strategies to promote such caution have been applied over the past decade, such as the development of guidelines for the management of medication of the older patients in EDs or software that automatically generates electronic alerts for PIMs or pDDIs in the prescription process.3 However, their effectiveness at ensuring safe medication prescription and administration has had limitations. For example, it was reported that a high percentage (35–96%) of automatically generated electronic alerts were often ignored by doctors because of inadequate alerts for a specific clinical situation or the intended prescription.29 To improve the situation, a more comprehensive review of prescription drugs based on clinical relevance and a better understanding of the unique medical environment of each country is needed. For this, doctor-pharmacist collaboration in ED may be the answer. Recent studies found that pharmacist-assisted medication reconciliation and integration system or academic detailing of physician residents provided by physician–pharmacist pairs contributed to reduce PIM prescription to older patients in ED practices.30,31\n\nThe strength of the current study was that it was able to accurately and completely collect patient-specific drug administration records and other details during ED visits using the EMR data collected from two large university-affiliated teaching hospitals. In addition, the PIM criteria used in this study contained more country-specific and substantial data than Beers Criteria which is commonly used criteria in Western countries. This allowed other medications that were not identified as potentially harmful by Beers Criteria (for example, opioid analgesics) to be reviewed in this study. Despite these strengths, this study has some limitations which should be interpreted carefully. First, since this study was conducted with ED data from two hospitals, it is difficult to generalize the study results in different environments. Second, although this study evaluated the incidence of PIM administration or pDDI in EDs, it did not evaluate the actual incidence of associated adverse drug reactions. Finally, this study was conducted in 2013. Nevertheless, we believe that the results of this study may help in promoting safe drug use in older patients in EDs, since PIMs and pDDIs are still recognized as important issues, especially in older patients.\n\nConclusion\nThis study demonstrated that older Korean patients were highly exposed to PIMs and medications with pDDIs in the ED. Therefore, healthcare providers in the EDs should carefully consider the risk of administering PMIs or medications with pDDIs, especially when treating female patients, patients who have been prescribed many medications in the ED, and patients who have stayed in the ED for a long time.\n\nAcknowledgments\nThe authors acknowledge the efforts of Department of Pharmacy of Gang Neung Asan Hospital and Kyung Hee University Hospital at Gangdong for collecting clinical data and providing administrative supports.\n\nDisclosure\nThe authors declare no potential conflicts of interests.\n==== Refs\nReferences\n1. Carpenter \nCR , Platts-Mills \nTF . Evolving prehospital, emergency department, and “inpatient” management models for geriatric emergencies\n. Clin Geriatr Med . 2013 ;29 (1 ):31 –47\n. doi:10.1016/j.cger.2012.09.003 23177599 \n2. Hwang \nU , Morrison \nRS . The geriatric emergency department\n. 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Clin Interv Aging . 2019 ;14 :1871 . doi:10.2147/CIA.S218849 31806945 \n15. Lim \nY-J , Kim \nH-Y , Choi \nJ , et al. Potentially inappropriate medications by beers criteria in older outpatients: prevalence and risk factors\n. Korean J Fam Med . 2016 ;37 (6 ):329 . doi:10.4082/kjfm.2016.37.6.329 27900070 \n16. Hwang \nH-J , Kim \nS-H , Lee \nKS . Potentially inappropriate medications in the elderly in Korean long-term care facilities\n. Drugs-Real World Outcomes . 2015 ;2 (4 ):355 –361\n. doi:10.1007/s40801-015-0046-1 26689669 \n17. Hong \nS , Lee \nJH , Chun \nEK , et al. Polypharmacy, inappropriate medication use, and drug interactions in older Korean patients with cancer receiving first-line palliative chemotherapy\n. Oncologist . 2020 ;25 (3 ):e502 . doi:10.1634/theoncologist.2019-0085 32162799 \n18. Kim \nDS , Jeon \nHL , Park \nJ , Bae \nS . Factors associated with potentially inappropriate medication use in elderly Koreans in an outpatient setting: a population-based study\n. J Am Geriatr Soc . 2016 ;64 (9 ):e21 –23\n. doi:10.1111/jgs.14267 27459338 \n19. Jeon \nHL , Park \nJ , Han \nE , Kim \nDS . Potentially inappropriate medication and hospitalization/emergency department visits among the elderly in Korea\n. Int J Qual Health Care . 2018 ;30 (1 ):50 –56\n. doi:10.1093/intqhc/mzx171 29438504 \n20. Brown \nJD , Hutchison \nLC , Li \nC , Painter \nJT , Martin \nBC . Predictive validity of the Beers and STOPP criteria to detect adverse drug events, hospitalizations, and emergency department visits in the United States\n. J Am Geriatr Soc . 2016 ;64 (1 ):22 . doi:10.1111/jgs.13884 26782849 \n21. Meurer \nWJ , Potti \nTA , Kerber \nKA , et al. Potentially inappropriate medication utilization in the emergency department visits by older adults: analysis from a nationally representative sample\n. Acad Emerg Med . 2010 ;17 (3 ):231 –237\n. doi:10.1111/j.1553-2712.2010.00667.x \n22. Chang \nC-B , Lai \nH-Y , Hwang \nS-J , et al. Prescription of potentially inappropriate medication to older patients presenting to the emergency department: a nationally representative population study\n. Sci Rep . 2018 ;8 (1 ):1 –8\n. doi:10.1038/s41598-018-30184-4 29311619 \n23. Hustey \nFM , Wallis \nN , Miller \nJ . Inappropriate prescribing in an older ED population\n. Am J Emerg Med . 2007 ;25 (7 ):804 –807\n. doi:10.1016/j.ajem.2007.01.018 17870486 \n24. Harrison \nL , O’Connor \nE , Jie \nC , Benzoni \nT , Renner \nCH , McCracken \nR . Potentially inappropriate medication prescribing in the elderly: is the beers criteria relevant in the emergency department today?\n\nAm J Emerg Med . 2019 ;37 (9 ):1734 –1737\n. doi:10.1016/j.ajem.2019.05.052 31176576 \n25. Al-Azayzih \nA , Alamoori \nR , Altawalbeh \nSM . Potentially inappropriate medications prescribing according to Beers criteria among elderly outpatients in Jordan: a cross sectional study\n. Pharm Pract (Granada) . 2019 ;17 (2 ):1439 . doi:10.18549/PharmPract.2019.2.1439 31275497 \n26. Fabbri \nE , Zoli \nM , Gonzalez-Freire \nM , Salive \nME , Studenski \nSA , Ferrucci \nL . Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research\n. J Am Med Dir Assoc . 2015 ;16 (8 ):640 –647\n. doi:10.1016/j.jamda.2015.03.013 25958334 \n27. Toepfer \nS , Bolbrinker \nJ , König \nM , Steinhagen-Thiessen \nE , Kreutz \nR , Demuth \nI . Potentially inappropriate medication in older participants of the Berlin aging study II (BASE-II)–Sex differences and associations with morbidity and medication use\n. PLoS One . 2019 ;14 (12 ):e0226511 . doi:10.1371/journal.pone.0226511 31887163 \n28. Rodriguez \nLAG , Cattaruzzi \nC , Troncon \nMG , Agostinis \nL . Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs\n. Arch Intern Med . 1998 ;158 (1 ):33 –39\n. doi:10.1001/archinte.158.1.33 9437376 \n29. Bajcar \nJM , Wang \nL , Moineddin \nR , Nie \nJX , Tracy \nCS , Upshur \nRE . From pharmaco-therapy to pharmaco-prevention: trends in prescribing to older adults in Ontario, Canada, 1997–2006\n. BMC Fam Pract . 2010 ;11 (1 ):75 . doi:10.1186/1471-2296-11-75 20929561 \n30. Liu \nYL , Chu \nLL , Su \nHC , et al. Impact of computer-based and pharmacist-assisted medication review initiated in the emergency department\n. J Am Geriatr Soc . 2019 ;67 (11 ):2298 –2304\n. doi:10.1111/jgs.16078 31335969 \n31. Moss \nJM , Bryan III \nWE , Wilkerson \nLM , et al. An interdisciplinary academic detailing approach to decrease inappropriate medication prescribing by physician residents for older veterans treated in the emergency department\n. J Pharm Pract . 2019 ;32 (2 ):167 –174\n. doi:10.1177/0897190017747424 29277130\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6336", "issue": "17()", "journal": "Therapeutics and clinical risk management", "keywords": "drug utilization review; drug–drug interactions; emergency department; older adults; potentially inappropriate medications", "medline_ta": "Ther Clin Risk Manag", "mesh_terms": null, "nlm_unique_id": "101253281", "other_id": null, "pages": "173-181", "pmc": null, "pmid": "33642859", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "27459338;31176576;10613941;23177599;16268411;28890140;25958334;31887163;30082816;24746437;26689669;9437376;17916122;29438504;31335969;17870486;32162799;20929561;19111015;26546335;26782849;14678335;24396090;27900070;23949970;29277130;31275497;31806945;20370754", "title": "Potentially Inappropriate Prescriptions to Older Patients in Emergency Departments in South Korea: A Retrospective Study.", "title_normalized": "potentially inappropriate prescriptions to older patients in emergency departments in south korea a retrospective study" }

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null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NORTRIPTYLINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", 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"medicinalproduct": "IMIPRAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", 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"primarysource": { "literaturereference": "KIM K., JUNG J., KIM J.T., OH J.M., KIM H.. POTENTIALLY INAPPROPRIATE PRESCRIPTIONS TO OLDER PATIENTS IN EMERGENCY DEPARTMENTS IN SOUTH KOREA: A RETROSPECTIVE STUDY. THER CLIN RISK MANAG. 2021?17:173?181", "literaturereference_normalized": "potentially inappropriate prescriptions to older patients in emergency departments in south korea a retrospective study", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20210520", "receivedate": "20210520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19277465, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "The treatment of Graves' hyperthyroidism (GD) complicated with malignancy is challenging, as anti-thyroid thionamide drugs (ATDs) and anti-cancer chemotherapy are both associated with a risk of neutropenia. Treatment with conventional ATDs, radioactive iodine (RAI) or potassium iodide (KI) was attempted in 8 patients with malignancy (34-80 years of age; 2 males and 6 females) in whom GD had been fortuitously diagnosed during a detailed systematic examination. Three patients requiring surgery were initially treated conventionally with methylmercaptoimidazole (MMI), MMI and KI or RAI (group A; one patient each). The patients became euthyroid on days 17-31 and underwent surgery on days 25-47. RAI therapy was administered to one patient after surgery. The patients were then treated with KI during chemotherapy. Five other patients who did not require surgery were initially treated with 100 mg KI monotherapy (group B). The serum free T4 level declined immediately in all of these patients, and they became euthyroid on days 7-18, remaining almost entirely euthyroid for more than 120 days. Anti-cancer chemotherapy was successfully completed for three of the patients while taking KI, despite the patients experiencing repeated episodes of anti-cancer chemotherapy-induced neutropenia. Our present findings suggest that, in patients with GD and malignancy, MMI + KI or RAI may be required if immediate surgery is scheduled, but KI monotherapy may be worth trying, if anti-cancer chemotherapy is scheduled, thus avoiding the possibility of thionamide-induced neutropenia.", "affiliations": "Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.", "authors": "Okamura|Ken|K|;Bandai|Sachiko|S|;Fujikawa|Megumi|M|;Sato|Kaori|K|;Kitazono|Takanari|T|", "chemical_list": "D013956:Antithyroid Agents; D007457:Iodine Radioisotopes; D011193:Potassium Iodide; D008713:Methimazole", "country": "Japan", "delete": false, "doi": "10.1507/endocrj.EJ20-0016", "fulltext": null, "fulltext_license": null, "issn_linking": "0918-8959", "issue": "67(7)", "journal": "Endocrine journal", "keywords": "Agranulocytosis; Antithyroid drug; Hyperthyroidism; Malignancy; Potassium iodide", "medline_ta": "Endocr J", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D013956:Antithyroid Agents; D005260:Female; D006111:Graves Disease; D006801:Humans; D006980:Hyperthyroidism; D007457:Iodine Radioisotopes; D008297:Male; D008713:Methimazole; D008875:Middle Aged; D009369:Neoplasms; D009503:Neutropenia; D011193:Potassium Iodide; D012307:Risk Factors; D013965:Thyroidectomy", "nlm_unique_id": "9313485", "other_id": null, "pages": "751-758", "pmc": null, "pmid": "32238669", "pubdate": "2020-07-28", "publication_types": "D016428:Journal Article", "references": null, "title": "Clinical experience of treating Graves' hyperthyroidism complicated with malignancy-The possible role of potassium iodide for avoiding the risk of thionamide-associated neutropenia.", "title_normalized": "clinical experience of treating graves hyperthyroidism complicated with malignancy the possible role of potassium iodide for avoiding the risk of thionamide associated neutropenia" }

[ { "companynumb": "JP-MYLANLABS-2020M1076178", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "POTASSIUM IODIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM IODIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POTASSIUM IODIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, RESTARTED AFTER SURGERY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POTASSIUM IODIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RADIOACTIVE IODINE SOLUTION" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIAMAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BASEDOW^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIAMAZOLE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypothyroidism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMURA K, BANDAI S, FUJIKAWA M, SATO K, KITAZONO T. CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. 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"primarysource": { "literaturereference": "OKAMURA K, BANDAI S, FUJIKAWA M, SATO K, KITAZONO T. CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. EDNOCR?J 2020?67(7):751?758.", "literaturereference_normalized": "clinical experience of treating graves hyperthyroidism complicated with malignancy the possible role of potassium iodide for avoiding the risk of thionamide associated neutropenia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200914", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18262135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "JP-MYLANLABS-2020M1076179", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. ENDOCR?J 2020?67(7):751?758.. 2020?67(7):751?758", "literaturereference_normalized": "clinical experience of treating graves hyperthyroidism complicated with malignancy the possible role of potassium iodide for avoiding the risk of thionamide associated neutropenia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200915", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18242713, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "JP-TEVA-2020-JP-1827312", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", 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"801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypothyroidism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMURA K, BANDAI S, FUJIKAWA M, SATO K, KITAZONO T. CLINICAL EXPERIENCE OF TREATING GRAVES^ HYPERTHYROIDISM COMPLICATED WITH MALIGNANCY?THE POSSIBLE ROLE OF POTASSIUM IODIDE FOR AVOIDING THE RISK OF THIONAMIDE?ASSOCIATED NEUTROPENIA. EDNOCR?J 2020?67(7):751?758.", "literaturereference_normalized": "clinical experience of treating graves hyperthyroidism complicated with malignancy the possible role of potassium iodide for avoiding the risk of thionamide associated neutropenia", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200928", "receivedate": "20200914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18262133, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Fusiform dilatation of the internal carotid artery (FDICA) is a well-described radiographic finding following resection of childhood craniopharyngioma (CP). A 39-year-old woman with right-sided FDICA was successfully treated for lesion enlargement with endovascular flow diversion, which has not been described in the literature.", "affiliations": "Department of Neurological Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, United States. Electronic address: [email protected].;Department of Neurological Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, United States.;Department of Neurological Surgery, Division of Neuroradiology, Emory University School of Medicine, Atlanta, GA, United States.;Department of Neurological Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, United States.;Department of Neurological Surgery, Division of Neuroradiology, Emory University School of Medicine, Atlanta, GA, United States.;Department of Radiology and Imaging Sciences, Division of Neuroradiology, Emory University School of Medicine, Atlanta, GA, United States.", "authors": "Reynolds|Matthew R|MR|;Heiferman|Daniel M|DM|;Boucher|Andrew B|AB|;Serrone|Joseph C|JC|;Barrow|Daniel L|DL|;Dion|Jacques E|JE|", "chemical_list": null, "country": "Scotland", "delete": false, "doi": "10.1016/j.jocn.2018.05.006", "fulltext": null, "fulltext_license": null, "issn_linking": "0967-5868", "issue": "54()", "journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia", "keywords": "Craniopharyngioma; Endovascular procedure; Fusiform aneurysm; Internal carotid artery; Stent", "medline_ta": "J Clin Neurosci", "mesh_terms": "D000328:Adult; D002343:Carotid Artery, Internal; D003397:Craniopharyngioma; D004106:Dilatation; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D019635:Neurosurgical Procedures; D010911:Pituitary Neoplasms; D011183:Postoperative Complications", "nlm_unique_id": "9433352", "other_id": null, "pages": "143-145", "pmc": null, "pmid": "29805079", "pubdate": "2018-08", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion-A case report and literature review.", "title_normalized": "fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion a case report and literature review" }

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FUSIFORM DILATATION OF THE INTERNAL CAROTID ARTERY FOLLOWING CHILDHOOD CRANIOPHARYNGIOMA RESECTION TREATED BY ENDOVASCULAR FLOW DIVERSION?A CASE REPORT AND LITERATURE REVIEW. JOURNAL OF CLINICAL NEUROSCIENCE. 2018?54:143?145", "literaturereference_normalized": "fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180731", "receivedate": "20180731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15220934, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "US-DRREDDYS-USA/USA/18/0103070", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTIC DILATATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076273", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTIC DILATATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subarachnoid haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug level above therapeutic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "REYNOLDS M, HEIFERMAN D, BOUCHER A, SERRONE J, BARROW D, DION J. FUSIFORM DILATATION OF THE INTERNAL CAROTID ARTERY FOLLOWING CHILDHOOD CRANIOPHARYNGIOMA RESECTION TREATED BY ENDOVASCULAR FLOW DIVERSION?A CASE REPORT AND LITERATURE REVIEW. J CLIN NEUROSCI. 2018?54:143?5.", "literaturereference_normalized": "fusiform dilatation of the internal carotid artery following childhood craniopharyngioma resection treated by endovascular flow diversion a case report and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20180903", "receivedate": "20180903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15343321, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Background. Network meta-analyses (NMAs) that compare treatments for a given condition allow physicians to identify which treatments have higher or lower probabilities of reducing the risks of disease complications or increasing the risks of treatment side effects. Translating these data into personalized treatment plans requires integration of NMA data with patient-specific pretreatment risk estimates and preferences regarding treatment objectives and acceptable risks. Methods. We introduce a modeling framework to integrate data probabilistically from NMAs with data on individualized patient risk estimates for disease outcomes, treatment preferences (such as willingness to incur greater side effects for increased life expectancy), and risk preferences. We illustrate the modeling framework by creating personalized plans for antipsychotic drug treatment and evaluating their effectiveness and cost-effectiveness. Results. Compared with treating all patients with the drug that yields the greatest quality-adjusted life-years (QALYs) on average (amisulpride), personalizing the selection of antipsychotic drugs for schizophrenia patients over the next 5 years would be expected to yield 0.33 QALYs (95% credible interval [crI]: 0.30-0.37) per patient at an incremental cost of $4849/QALY gained (95% crI: dominant-$12,357), versus 0.29 and 0.04 QALYs per patient when accounting for only risks or preferences, respectively, but not both. Limitations. The analysis uses a linear, additive utility function to reflect patient treatment preferences and does not consider potential variations in patient time discounting. Conclusions. Our modeling framework rigorously computes what physicians normally have to do mentally. By integrating 3 key components of personalized medicine-evidence on efficacy, patient risks, and patient preferences-the modeling framework can provide personalized treatment decisions to improve patient health outcomes.", "affiliations": "Department of Management Science and Engineering, Stanford University, Stanford, CA, USA.;Department of Management Science and Engineering, Stanford University, Stanford, CA, USA.;Center for Primary Care, Harvard Medical School, Boston, MA, USA.", "authors": "Weyant|Christopher|C|0000-0003-2609-9486;Brandeau|Margaret L|ML|;Basu|Sanjay|S|0000-0002-0599-6332", "chemical_list": "D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.1177/0272989X19884927", "fulltext": null, "fulltext_license": null, "issn_linking": "0272-989X", "issue": "39(8)", "journal": "Medical decision making : an international journal of the Society for Medical Decision Making", "keywords": "medical decision making; personalized medicine; schizophrenia", "medline_ta": "Med Decis Making", "mesh_terms": "D014150:Antipsychotic Agents; D003198:Computer Simulation; D003657:Decision Making; D006801:Humans; D000071076:Network Meta-Analysis; D057240:Patient Preference; D057285:Precision Medicine; D019057:Quality-Adjusted Life Years; D018570:Risk Assessment; D012309:Risk-Taking; D012559:Schizophrenia", "nlm_unique_id": "8109073", "other_id": null, "pages": "998-1009", "pmc": null, "pmid": "31707910", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "22927695;17909124;9603539;21268053;28696023;27832461;29649252;27434443;25084808;25992305;26626279;28269836;26009228;28919117;27955666;19884297;23810019;25986470;24968989;29477251;20535326;15916472;22025428;28675302;29146652;10834905;27799749;16595571;31077814;22197518;19744297;25950615;25128056;9008519", "title": "Personalizing Medical Treatment Decisions: Integrating Meta-analytic Treatment Comparisons with Patient-Specific Risks and Preferences.", "title_normalized": "personalizing medical treatment decisions integrating meta analytic treatment comparisons with patient specific risks and preferences" }

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{ "abstract": "Stress-induced changes in pharmacokinetics can significantly alter the plasma levels of some drugs such as clozapine. This report describes the case of a middle-aged man with schizoaffective disorder, bipolar type who showed sustained elevation in clozapine levels 3 days after discontinuation. Before the clozapine levels were drawn, he had developed acute bacterial pneumonia and signs of acute bacterial meningitis followed by neuroleptic malignant syndrome after he received multiple doses of intravenous haloperidol for worsening psychosis and aggressive behavior. Existing literature on this topic is also reviewed to investigate potential reasons for sustained clozapine levels during acute inflammatory stress and neuroleptic malignant syndrome.", "affiliations": "Department of Psychiatry, Good Samaritan Regional Medical Center, Corvallis, Oregon, USA.;Napa State Hospital, 2100 Napa Vallejo Hwy, Napa, CA 94558. [email protected].", "authors": "Wagner|Abigail|A|;Shad|Mujeeb U|MU|", "chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "2155-7780", "issue": "22(4)", "journal": "The primary care companion for CNS disorders", "keywords": null, "medline_ta": "Prim Care Companion CNS Disord", "mesh_terms": "D000208:Acute Disease; D014150:Antipsychotic Agents; D003024:Clozapine; D006801:Humans; D008297:Male; D016920:Meningitis, Bacterial; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D018410:Pneumonia, Bacterial; D011618:Psychotic Disorders", "nlm_unique_id": "101547532", "other_id": null, "pages": null, "pmc": null, "pmid": "32628372", "pubdate": "2020-07-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Relationship Between Clozapine Levels and Acute Inflammatory Stress.", "title_normalized": "relationship between clozapine levels and acute inflammatory stress" }

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RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. PRIM CARE COMP CNS DISORDERS. 2020?22(4)? 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null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA PNEUMOCOCCAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20190416" } }, "primarysource": { "literaturereference": "SHAD M, WAGNER . RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. THE PRIMARY CARE COMPANION TO CNS DISORDERS. 2020?22 (4):.", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200908", "receivedate": "20200717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18037162, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-TEVA-2020-US-1812722", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": 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null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-disease interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Neuroleptic malignant syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "WAGNER A, SHAD MU. RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. PRIM?CARE?COMP?CNS?DISORDERS 2020?22(4):NO PAGINATION.", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200828", "receivedate": "20200812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18142795, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-ACCORD-190932", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": null, 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"reactionmeddrapt": "Pneumonia streptococcal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug-disease interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis bacterial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201904" } }, "primarysource": { "literaturereference": "WAGNER A, SHAD M. RELATIONSHIP BETWEEN CLOZAPINE LEVELS AND ACUTE INFLAMMATORY STRESS. PRIM CARE COMPANION CNS DISORD. 2020?22(4):19BR02586", "literaturereference_normalized": "relationship between clozapine levels and acute inflammatory stress", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200731", "receivedate": "20200718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18039173, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Our aim is to study unanticipated cardiotoxicity associated with the use of anticancer targeted agents, a problem that remains poorly understood. Using diagnosis codes, we retrospectively identified patients with both hematologic malignancies (HM) and cardiovascular diseases (n = 820 patients). Cardiotoxicity was defined per published criteria. The targeted agents of interest included tyrosine kinase inhibitors, proteasome inhibitors, monoclonal antibodies, and immunomodulatory agents. Patients found with cardiotoxicity (n = 29) were compared with 70 case-matched reference subjects. Median time from targeted therapy exposure to cardiotoxicity was 132 days. A higher percentage of patients had prior exposure to anthracyclines in study versus reference group (65.5 vs. 42.8%, P = 0.04), however, did not stay significant in multivariate analysis. Two variables were significant predictors, prior of DVT/PE and Karnofsky score of ≥ 80% (P ≤ 0.011). Only 2 study group patients died of cardiac causes. Most cardiotoxicity patients (23/29) had remained stable or improved, while 21 patients received further chemotherapy. OS was lower in the study group (P = 0.018) versus the reference group. In conclusion, a small number patients with HM experience unanticipated cardiotoxicity with low related mortality. Risk of cardiotoxicity was significantly associated with history of DVT/PE. Most patients do well, but despite that, their OS is significantly poorer.", "affiliations": "Division of Hematology/Oncology, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL, 32610, USA.;Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.;Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.;Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.;Center for Personalized Diagnostics, Biodesign Inst, Arizona State University, Tempe, AZ, USA.;Division of Hematology/Oncology, Department of Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL, 32610, USA. [email protected].", "authors": "Shah|Chintan|C|;Gong|Yan|Y|;Szady|Anita|A|;Sun|Qian|Q|;Pepine|Carl J|CJ|;Langaee|Taimour|T|;Lucas|Alexandra R|AR|;Moreb|Jan S|JS|0000-0001-9330-7500", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": "10.1007/s12012-017-9429-8", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-7905", "issue": "18(2)", "journal": "Cardiovascular toxicology", "keywords": "Cardiotoxicity; Hematologic malignancies; Targeted therapy", "medline_ta": "Cardiovasc Toxicol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D066126:Cardiotoxicity; D005260:Female; D006331:Heart Diseases; D019337:Hematologic Neoplasms; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D020246:Venous Thrombosis", "nlm_unique_id": "101135818", "other_id": null, "pages": "184-191", "pmc": null, "pmid": "29022233", "pubdate": "2018-04", "publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "10637245;11287972;11807147;11870163;15795913;16075055;16862153;17319909;18054041;18415035;18490248;18591451;19520246;19638707;20007921;20842465;22044821;22997448;23623503;24489948;24963043;25433360;25733089;26331915;26671818;26735901;26742998;26771810;26899778;26968791;27081036;27123262;27388042;27800661;27813147;28233150", "title": "Unanticipated Cardiotoxicity Associated with Targeted Anticancer Therapy in Patients with Hematologic Malignancies Patients: Natural History and Risk Factors.", "title_normalized": "unanticipated cardiotoxicity associated with targeted anticancer therapy in patients with hematologic malignancies patients natural history and risk factors" }

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CARDIOVASC-TOXICO 2018?18(2):184-191.", "literaturereference_normalized": "unanticipated cardiotoxicity associated with targeted anticancer therapy in patients with hematologic malignancies patients natural history and risk factors", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180419", "receivedate": "20180419", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14780172, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-TEVA-2018-US-882649", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022249", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" } ], "patientagegroup": null, "patientonsetage": "88", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH C, GONG Y, SZADY A, SUN Q, PEPINE CJ, LANGAEE T, ET AL. UNANTICIPATED CARDIOTOXICITY ASSOCIATED WITH TARGETED ANTICANCER THERAPY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES PATIENTS: NATURAL HISTORY AND RISK FACTORS. CARDIOVASC-TOXICO 2018?18(2):184-191.", "literaturereference_normalized": "unanticipated cardiotoxicity associated with targeted anticancer therapy in patients with hematologic malignancies patients natural history and risk factors", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180419", "receivedate": "20180419", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14780132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "Isoniazid is an anti-tuberculosis drug, used commonly for treatment and prophylaxis of tuberculosis. Acute isoniazid intoxication is characterized by a clinical triad consisting of metabolic acidosis resistant to treatment with sodium bicarbonate, seizures which may be fatal and refractory to standard anticonvulsant therapy, and coma. Treatment requires admission to the intensive care unit for ventilatory support, management of seizures and metabolic acidosis. Pyridoxine, in a dose equivalent to the amount of isoniazid ingested, is the only effective antidote. We report the successful treatment of two isoniazid intoxication cases: the case of a child developing an accidental acute isoniazid intoxication and an adult case of isoniazid intoxication with the intent of suicide.", "affiliations": "Department of Anesthesiology and Reanimation, Celal Bayar University, Manisa, Turkey.", "authors": "Topcu|I|I|;Yentur|E A|EA|;Kefi|A|A|;Ekici|N Z|NZ|;Sakarya|M|M|", "chemical_list": "D000927:Anticonvulsants; D000995:Antitubercular Agents; D014803:Vitamin B Complex; D002606:Charcoal; D017693:Sodium Bicarbonate; D013874:Thiopental; D011736:Pyridoxine; D003975:Diazepam; D007538:Isoniazid", "country": "United States", "delete": false, "doi": "10.1177/0310057X0503300416", "fulltext": null, "fulltext_license": null, "issn_linking": "0310-057X", "issue": "33(4)", "journal": "Anaesthesia and intensive care", "keywords": null, "medline_ta": "Anaesth Intensive Care", "mesh_terms": "D000138:Acidosis; D000208:Acute Disease; D000293:Adolescent; D000927:Anticonvulsants; D000995:Antitubercular Agents; D002606:Charcoal; D002648:Child; D003128:Coma; D003975:Diazepam; D005260:Female; D005751:Gastric Lavage; D006801:Humans; D007442:Intubation, Intratracheal; D007538:Isoniazid; D011736:Pyridoxine; D012640:Seizures; D017693:Sodium Bicarbonate; D013406:Suicide, Attempted; D013874:Thiopental; D014803:Vitamin B Complex", "nlm_unique_id": "0342017", "other_id": null, "pages": "518-20", "pmc": null, "pmid": "16119496", "pubdate": "2005-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication.", "title_normalized": "seizures metabolic acidosis and coma resulting from acute isoniazid intoxication" }

[ { "companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2022-05209", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202610", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Topcu I, Yentur EA, Kefi A, Ekici NZ et al.. Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication. Anaesth Intensive Care. 2005;33(4):518-20", "literaturereference_normalized": "seizures metabolic acidosis and coma resulting from acute isoniazid intoxication", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20220601", "receivedate": "20220601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20899628, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2022-05207", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202610", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Topcu I, Yentur EA, Kefi A, Ekici NZ, et.al. Seizures, metabolic acidosis and coma resulting from acute isoniazid intoxication. Anaesth Intensive Care. 2005;33(4):518-520", "literaturereference_normalized": "seizures metabolic acidosis and coma resulting from acute isoniazid intoxication", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20220601", "receivedate": "20220601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20899632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" } ]

{ "abstract": "BACKGROUND\nTo assess feasibility, acute toxicity, and efficacy of intraventricular methotrexate administered as part of the primary therapy in medulloblastoma.\n\n\nMETHODS\nFrom 2001 to 2007, 240 patients < 22 years from 61 treatment centres were registered. Patients received 2-3 cycles of intraventricular methotrexate with systemic chemotherapy in three different treatment arms of the prospective multicentre trial HIT2000 (150 children > 4 years with metastatic, 59 < 4 years with non-metastatic, 31 < 4 years with metastatic medulloblastoma).\n\n\nRESULTS\n211 patients received an intraventricular access device with a subcutaneous reservoir for the application of chemotherapy. Reservoir-associated complications were documented in 57 (27%) patients, mostly due to infection (n = 32) and reservoir malfunction (n = 19), requiring removal in 39 (18%) patients. Acute neurotoxicity likely associated with intraventricular MTX was observed in 9/202 documented patients. Toxicity was usually mild, apart from one therapy-associated death due to toxic oedema followed by seizures. Of 519 treatment cycles including intraventricular methotrexate, 226 (43%) were reduced or omitted, most frequently due to the absence of an intraventricular device. Survival rates were higher in patients receiving ⩾ 75% of the scheduled intraventricular methotrexate dose compared to those receiving < 75% in both univariate and multivariate models (event-free survival (EFS), 61.5 versus 46.2%, p = 0.004; OS, 75.5% versus 60.4%, p = 0.015; hazard ratio: EFS 1.723, p = 0.016; OS 1.648, p = 0.051).\n\n\nCONCLUSIONS\nIntraventricular methotrexate therapy was feasible and mostly well tolerated. Infections were the most frequent complication. A higher cumulative dose of intraventricular methotrexate was associated with better survival. Further evaluation of efficacy and late effects is warranted.", "affiliations": "Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Woman's and Children's Health, University Hospital Leipzig, Leipzig, Germany.;Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany.;Department of Pediatric Oncology, University of Wuerzburg, Germany.;Pediatrics III, University Hospital of Essen, Germany.;Department of Pediatric Oncology, University of Wuerzburg, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: [email protected].", "authors": "Pompe|Raisa S|RS|;von Bueren|André O|AO|;Mynarek|Martin|M|;von Hoff|Katja|K|;Friedrich|Carsten|C|;Kwiecien|Robert|R|;Treulieb|Wiebke|W|;Lindow|Christine|C|;Deinlein|Frank|F|;Fleischhack|Gudrun|G|;Kuehl|Joachim|J|;Rutkowski|Stefan|S|", "chemical_list": "D008727:Methotrexate", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0959-8049", "issue": "51(17)", "journal": "European journal of cancer (Oxford, England : 1990)", "keywords": "Brain tumours; Chemotherapy; Intraventricular; Medulloblastoma; Methotrexate; Treatment", "medline_ta": "Eur J Cancer", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007223:Infant; D007239:Infections; D007276:Injections, Intraventricular; D008297:Male; D008527:Medulloblastoma; D008727:Methotrexate; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care; D016016:Proportional Hazards Models; D011446:Prospective Studies; D055815:Young Adult", "nlm_unique_id": "9005373", "other_id": null, "pages": "2634-42", "pmc": null, "pmid": "26346136", "pubdate": "2015-11", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy.", "title_normalized": "intraventricular methotrexate as part of primary therapy for children with infant and or metastatic medulloblastoma feasibility acute toxicity and evidence for efficacy" }

[ { "companynumb": "DE-MYLANLABS-2015M1046321", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "050", "drugauthorizationnumb": "201529", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDULLOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Areflexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "POMPE RS, VON BUEREN AO, MYNAREK M, VON HOFF K, FRIEDRICH C, KWIECIEN R, ET AL. INTRAVENTRICULAR METHOTREXATE AS PART OF PRIMARY THERAPY FOR CHILDREN WITH INFANT AND/OR METASTATIC MEDULLOBLASTOMA: FEASIBILITY, ACUTE TOXICITY AND EVIDENCE FOR EFFICACY. EUR-J-CANCER 2015? 51(17):2634-42.", "literaturereference_normalized": "intraventricular methotrexate as part of primary therapy for children with infant and or metastatic medulloblastoma feasibility acute toxicity and evidence for efficacy", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20151223", "receivedate": "20151223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11862773, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]

{ "abstract": "Eptifibatide is a glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitor which prevents platelet activation. The mechanism in which eptifibatide causes profound thrombocytopenia is poorly understood. One hypothesis suggests antibody-dependent pathways which cause thrombocytopenia upon subsequent reexposure to eptifibatide. This case reports acute profound thrombocytopenia (platelets < 20 × 103/mm3) within 24 hours of administration. Alveolar hemorrhage occurred during a second eptifibatide infusion 5 days after initial asymptomatic eptifibatide treatment. Case Presentation. A 50-year-old male presenting with a STEMI was treated with eptifibatide during cardiac catheterization. Twelve hours posttreatment, the patient encountered profound thrombocytopenia and hemoptysis. The patient was briefly intubated for airway protection. The patient was stabilized after receiving platelet transfusion and fully recovered.\nThis is one of several cases reported on eptifibatide causing acute profound thrombocytopenia and subsequent alveolar hemorrhage. This case supports the theory in which antibodies contribute to eptifibatide-induced thrombocytopenia.", "affiliations": "Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.;Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.;Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.;Michigan State University College of Osteopathic Medicine, 965 Wilson Road, East Lansing, MI 48824, USA.;Michigan State University College of Osteopathic Medicine, 965 Wilson Road, East Lansing, MI 48824, USA.;Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA.", "authors": "Byrd|Gregory|G|https://orcid.org/0000-0002-3829-1793;Custovic|Sabina|S|;Byrd|David|D|;Ingrassia Miano|Deanna|D|;Bathla|Jasdeep|J|;Attallah|Antonious|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2021/8817067", "fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420\n2090-6439\nHindawi\n\n10.1155/2021/8817067\nCase Report\nAcute Profound Thrombocytopenia Induced by Eptifibatide Causing Diffuse Alveolar Hemorrhage\nhttps://orcid.org/0000-0002-3829-1793\nByrd Gregory [email protected]\n1\nCustovic Sabina 1\nByrd David 1\nIngrassia Miano Deanna 2\nBathla Jasdeep 2\nAttallah Antonious 1\n1Department of Internal Medicine, Ascension Macomb-Oakland Hospital, 11800 12 Mile Road, Warren, MI 48093, USA\n2Michigan State University College of Osteopathic Medicine, 965 Wilson Road, East Lansing, MI 48824, USA\nAcademic Editor: Kenneth S. Waxman\n\n2021\n15 7 2021\n2021 881706723 7 2020\n16 6 2021\nCopyright © 2021 Gregory Byrd et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nEptifibatide is a glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitor which prevents platelet activation. The mechanism in which eptifibatide causes profound thrombocytopenia is poorly understood. One hypothesis suggests antibody-dependent pathways which cause thrombocytopenia upon subsequent reexposure to eptifibatide. This case reports acute profound thrombocytopenia (platelets < 20 × 103/mm3) within 24 hours of administration. Alveolar hemorrhage occurred during a second eptifibatide infusion 5 days after initial asymptomatic eptifibatide treatment. Case Presentation. A 50-year-old male presenting with a STEMI was treated with eptifibatide during cardiac catheterization. Twelve hours posttreatment, the patient encountered profound thrombocytopenia and hemoptysis. The patient was briefly intubated for airway protection. The patient was stabilized after receiving platelet transfusion and fully recovered.\n\nConclusion\n\nThis is one of several cases reported on eptifibatide causing acute profound thrombocytopenia and subsequent alveolar hemorrhage. This case supports the theory in which antibodies contribute to eptifibatide-induced thrombocytopenia.\n==== Body\n1. Introduction\n\nEptifibatide is a glycoprotein IIb/IIIa receptor inhibitor which works to prevent cross-linkage and platelet plug formation. Eptifibatide is used as standard antithrombotic therapy in the management of acute coronary syndrome (ACS) with unstable angina (UA) or non-ST elevation myocardial infarctions (NSTEMI), as well as in those undergoing percutaneous coronary intervention (PCI). Despite clinical efficacy, acute profound thrombocytopenia within 24 hours of treatment may develop with eptifibatide. Diffuse alveolar hemorrhage (DAH), another rare complication of GP IIb/IIIa inhibitor therapy, is diagnosed using typical symptoms of dyspnea and hemoptysis in addition to radiographic changes [1, 2]. Here, we present a case in which eptifibatide causes thrombocytopenia and alveolar hemorrhage upon second exposure.\n\n2. Case Presentation\n\nThis case outlines a 50-year-old male with past medical history significant for diabetes, hypertension, and coronary artery disease (CAD) who presented to the hospital with chest pain. Five days prior, the patient underwent cardiac catheterization with intervention; 3 stents were placed in the left anterior descending artery. Upon presentation, the patient was found to have an inferior-posterior STEMI. He received multiple balloon angioplasties to a 100% occluded first obtuse marginal artery with in-stent thrombosis. At this time, the patient was on aspirin and Ticagrelor. He was further treated with eptifibatide during the catheterization; a double bolus was given during the case and was to be continued for 12 hours thereafter. The patient developed a severe cough and mild-moderate hemoptysis. In subsequent chest X-rays, diffuse opacities were seen, and the patient was eventually intubated for airway protection (Figure 1). The patient's platelets decreased from 370k to 5k within 12 hours. It is worth noting that the patient was treated with eptifibatide during his initial catheterization 5 days prior as well, with no complications. Due to his acute profound thrombocytopenia and persistent hemoptysis, the patient received 1 unit of platelets; the Ticagrelor and eptifibatide were discontinued. Soon after, his platelets began to rebound. In addition, the patient was extubated the following morning. The patient did not require further intervention, made full recovery, and was discharged 9 days later.\n\n3. Discussion\n\nToday, antiplatelet use is standard in patients with ACS undergoing cardiac catheterization. Eptifibatide works by reversibly inhibiting platelet activation by binding to GP IIb/IIIa receptors on the surface of the platelets. The GP IIb/IIIa receptor is an integrin receptor found exclusively on the surface of the platelets. These receptors respond to components such as von Willebrand factor (vWF), fibronectin, and fibrinogen, which in turn activate clotting [3, 4]. After the receptor is activated, it leads to cross-linking of platelets causing aggregation and thus the formation of a thrombus. Eptifibatide acts as a ligand mimetic; it adheres to the GP IIb/IIIa recognition site and blocks vWF, fibronectin, and fibrinogen from binding, ultimately inhibiting platelet aggregation [5]. The GP IIb/IIIa receptor is especially interesting for several reasons. One reason is that it appears to be hidden when the platelet is not activated [3]. Additionally, there is a staggering amount of the receptors on each platelet, an estimated 50,000 receptors/cell, giving platelets a powerful ability to aggregate and form a clot [3]. This is likely the reason why GP IIb/IIIa inhibitors are very successful at inhibiting platelet aggregation (Figure 2).\n\nDrug-induced thrombocytopenia is a known complication of GP IIb/IIIa inhibitors [6, 7]. Acute profound thrombocytopenia, commonly defined as platelets < 20 × 103/mm3 within 24 hours of administration, is a rare complication of eptifibatide [8]. In our patient's case, a drop of platelets from 370k to 5k within 12 hours of eptifibatide reexposure, as well as platelet rebound after eptifibatide discontinuation, leads us to believe that this was an instance of drug-induced thrombocytopenia. Drug-induced thrombocytopenia can be confirmed with serum eptifibatide-dependent platelet-reactive antibody testing; however, these labs were not conducted in this particular case [9].\n\nThe estimated occurrence of thrombocytopenia with eptifibatide use is approximately 3%, and acute profound thrombocytopenia occurs around 0.1-1% [4]. According to a database published by the University of Oklahoma which analyzed cases of eptifibatide-induced thrombocytopenia, only 16 of 34 reported cases had bleeding associated with profound thrombocytopenia. The database specifically noted that 10 of the 16 cases had major bleeding (i.e., melena, gross hematuria, and excessive epistaxis). Six of the 16 cases had minor bleeding or trivial bleeding (i.e., petechiae and purpura) [10].\n\nThe mechanism of how eptifibatide causes thrombocytopenia is currently unknown. Mechanisms involving both antibody-dependent and antibody-independent pathways have been proposed. One review found several independent risk factors for thrombocytopenia, including age > 65, low BMI, and a baseline platelet count of <180k [11]. The fact that thrombocytopenia can occur after the first dose of eptifibatide supports current theories of an antibody-independent pathway. However, there is some data to suggest that there are either naturally occurring antibodies against the ligand binding sites where these antiplatelet molecules act [12, 13]. One review found that 5 out of 5 patients who developed thrombocytopenia had high IgG titers with cross-reactivity to GP IIb/IIIa, while 1 of the 5 patients had high IgG levels prior to eptifibatide administration. This data is suggestive of both mechanisms playing a role [9].\n\nEptifibatide-induced thrombocytopenia is a clinical diagnosis. The clinical picture of eptifibatide-induced thrombocytopenia appears as a rapidly dropping platelet count that is quickly reversed after discontinuation of the drug. The most important differentials to rule out are heparin-induced thrombocytopenia and pseudothrombocytopenia. Most other disorders are easily excluded due to a normal platelet count prior to the administration of the drug. In addition, typically, platelet counts only drop below 20k in eptifibatide-induced thrombocytopenia; other diagnoses rarely dip below this threshold.\n\nAdequate treatment of eptifibatide-induced thrombocytopenia typically only requires removal of the offending agent, and platelets usually recover to near-normal levels within several days [12]. If profound thrombocytopenia is present or clinically significant bleeding occurs, both of which were seen in this patient, platelets may be transfused [12].\n\n4. Conclusion\n\nThis case highlights another example of eptifibatide-induced thrombocytopenia and diffuse alveolar hemorrhage. Furthermore, this case may give more weight to the theory that drug-induced thrombocytopenia is driven by antibodies. Although this case does not prove this theory, it is consistent with the theory, as our patient did not have any adverse effects with his first exposure to eptifibatide.\n\nConsent\n\nConsent was obtained from the patient.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 (a) Approximately 24 hours prior to the development of diffuse pulmonary hemorrhage. (b) After the development of severe cough and hemoptysis which required airway protection through intubation.\n\nFigure 2 Flow chart demonstrating platelet activation via GP IIb/IIIa activation. Eptifibatide and similar drugs (red) inhibit the aggregation pathway by blocking GP IIb/IIIa functionality.\n==== Refs\n1 Sadeghi Ghahrodi M. Mahmoody Y. Sheikhlou H. Aalaei Andabili H. Alveolar hemorrhage: a rare complication of eptifibatide (glycoprotein IIb/IIIa inhibitor) International Cardiovascular Research Journal 2011 5 4 151 152 10.5812/icrj.4369 2-s2.0-84859860793\n2 Mikkilineni H. Bruhl S. R. Colyer W. R. Pandya U. A retrospective analysis and case series of glycoprotein IIb/IIIa inhibitor associated diffuse alveolar hemorrhage: two case reports Cases Journal 2009 2 1, article 8553 10.4076/1757-1626-2-8553 2-s2.0-77953383369\n3 Coller B. S. Platelets and thrombolytic therapy New England Journal of Medicine 1990 322 1 33 42 10.1056/NEJM199001043220107 2-s2.0-0025097994\n4 Graidis C. Golias C. Dimitriadis D. Eptifibatide-induced acute profound thrombocytopenia: a case report BMC Research Notes 2014 7 1 p. 107 10.1186/1756-0500-7-107 2-s2.0-84899478046\n5 Visentin G. P. Liu C. Y. Drug-induced thrombocytopenia Hematology/Oncology Clinics of North America 2007 21 4 685 696 10.1016/j.hoc.2007.06.005 2-s2.0-34547114992 17666285\n6 Bougie D. W. Wilker P. R. Wuitschick E. D. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa Blood 2002 100 6 2071 2076 10.1182/blood.V100.6.2071 12200368\n7 Aster R. H. Curtis B. R. Bougie D. W. Thrombocytopenia resulting from sensitivity to GPIIb-IIIa inhibitors Seminars in Thrombosis and Hemostasis 2004 30 5 569 577 10.1055/s-2004-835677 2-s2.0-7044269109 15497099\n8 Nagge J. Jackevicius C. Dzavik V. Ross J. R. Seidelin P. Acute profound thrombocytopenia associated with eptifibatide therapy Pharmacotherapy 2003 23 3 374 379 10.1592/phco.23.3.374.32107 2-s2.0-0037369974 12627937\n9 Attaya S. Kanthi Y. Aster R. McCrae K. Acute profound thrombocytopenia with second exposure to eptifibatide associated with a strong antibody reaction Platelets 2009 20 1 64 67 10.1080/09537100802592676 2-s2.0-61649127808 19172524\n10 George J. N. Drug-induced thrombocytopenia Annals of Internal Medicine 1998 129 11,_Part_1 886 890 10.7326/0003-4819-129-11_part_1-199812010-00009 9867731\n11 Said S. M. Hahn J. Schleyer E. Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia Clinical Research in Cardiology 2007 96 2 61 69 10.1007/s00392-006-0459-7 2-s2.0-33846897804 17146606\n12 George J. N. Aster R. H. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management Hematology 2009 2009 1 153 158 10.1182/asheducation-2009.1.153 2-s2.0-77949434753 20008194\n13 Tempelhof M. W. Benzuly K. H. Fintel D. Krichavsky M. Z. Eptifibatide-induced thrombocytopenia: with thrombosis and disseminated intravascular coagulation immediately after left main coronary artery percutaneous coronary angioplasty Texas Heart Institute Journal 2012 39 1 86 91 22412237\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2021()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "8817067", "pmc": null, "pmid": "34327026", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "15497099;24564943;9867731;17666285;12200368;17146606;22412237;19172524;2264841;12627937;20008194;19830082", "title": "Acute Profound Thrombocytopenia Induced by Eptifibatide Causing Diffuse Alveolar Hemorrhage.", "title_normalized": "acute profound thrombocytopenia induced by eptifibatide causing diffuse alveolar hemorrhage" }

[ { "companynumb": "US-009507513-2108USA003216", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TICAGRELOR" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICAGRELOR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EPTIFIBATIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "020718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "DOUBLE BOLUS,CONTINUED FOR 12 HOURS THEREAFTER", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTEGRILIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary alveolar haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction issue", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BYRD G, CUSTOVIC S, BYRD D, MIANO DI, BATHLA J, ATTALLAH A. ACUTE PROFOUND THROMBOCYTOPENIA INDUCED BY EPTIFIBATIDE CAUSING DIFFUSE ALVEOLAR HEMORRHAGE. 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ACUTE PROFOUND THROMBOCYTOPENIA INDUCED BY EPTIFIBATIDE CAUSING DIFFUSE ALVEOLAR HEMORRHAGE. CASE REPORTS IN CRITICAL CARE. 2021?1?3", "literaturereference_normalized": "acute profound thrombocytopenia induced by eptifibatide causing diffuse alveolar hemorrhage", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19716016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.", "affiliations": "Liver Transplant Unit, Department of Gastroenterology, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Pathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, Barcelona, Spain.;Liver Transplant Unit, Department of Gastroenterology, Bellvitge University Hospital, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, Barcelona, Spain.;Liver Transplant Unit, Department of Pathology, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain.;Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.", "authors": "Baliellas|Carme|C|0000-0002-3641-6484;Lladó|Laura|L|0000-0002-3717-3306;Serrano|Teresa|T|0000-0003-4679-2771;Gonzalez-Vilatarsana|Emma|E|;Cachero|Alba|A|;Lopez-Dominguez|Josefina|J|;Petit|Anna|A|;Fabregat|Joan|J|", "chemical_list": "D000906:Antibodies", "country": "United States", "delete": false, "doi": "10.1111/ajt.16689", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "21(11)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "liver allograft function/dysfunction; liver transplantation/hepatology; nical research/practice; rejection: antibody-mediated (ABMR)", "medline_ta": "Am J Transplant", "mesh_terms": "D000906:Antibodies; D005260:Female; D006084:Graft Rejection; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008875:Middle Aged", "nlm_unique_id": "100968638", "other_id": null, "pages": "3775-3779", "pmc": null, "pmid": "34008326", "pubdate": "2021-11", "publication_types": "D002363:Case Reports", "references": null, "title": "Sinusoidal obstruction syndrome as a manifestation of acute antibody-mediated rejection after liver transplantation.", "title_normalized": "sinusoidal obstruction syndrome as a manifestation of acute antibody mediated rejection after liver transplantation" }

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SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. 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SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY?MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. UNK. 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SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY?MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. AM J TRANSPLANT. 2021 MAY 19. 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L, SERRANO T, GONZALEZ?VILATARSANA E, CACHERO A, LOPEZ?DOMINGUEZ J ET AL. SINUSOIDAL OBSTRUCTION SYNDROME AS A MANIFESTATION OF ACUTE ANTIBODY?MEDIATED REJECTION AFTER LIVER TRANSPLANTATION. AM J TRANSPLANT. 2021", "literaturereference_normalized": "sinusoidal obstruction syndrome as a manifestation of acute antibody mediated rejection after liver transplantation", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210901", "receivedate": "20210901", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19770539, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Convulsive seizures are known to cause severe cardiopulmonary changes and increased autonomic activity. Limited reports describe peri-ictal cardiac arrhythmias such as atrial fibrillation (AF) with generalized tonic-clonic seizures (GTCS). We present a unique case of a healthy 23-year-old male patient with new onset prolonged AF in the setting of new onset seizures, occurring on three independent occasions. Over two years, our patient had multiple hospitalizations for seizures with an electrocardiogram (ECG) diagnosis of AF made on three different occasions, occurring during his post-ictal state (all within 30 min of seizure onset). These seizures were never captured by electroencephalography (EEG) or witnessed by the medical staff, but were reported by family and/or reviewed on video provided by them. After his first GTCS, his AF persisted and was medically cardioverted. Two additional instances of AF after witnessed GTCS have been captured. After his second unprovoked seizure, an anti-seizure drug (ASD) was prescribed. A multi-disciplinary approach may be adopted to address comorbidities associated with seizures. Aggressive evaluation and treatment should be employed for newly diagnosed and refractory seizure patients associated with arrhythmias, in our case AF. Peri-ictal arrhythmias may be considered a potential marker for increased sudden unexpected death in epilepsy (SUDEP) risk.", "affiliations": "Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Medicine, University of Louisville, 501 East Broadway, Suite 100, Louisville, KY 40202, USA.;Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.;Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.;Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA.", "authors": "Elnazeir|Marwa|M|;Badugu|Pradeepthi|P|;Narayanan|Siddharth|S|;Hussain|Abid|A|;Bhagat|Riwaj N M N|RNMN|;Jones|Christopher M|CM|;Holiday|Victoria N|VN|;Evans|Miles S|MS|;Palade|Adriana E|AE|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ebr.2019.100343", "fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864 Elsevier \n\nS2589-9864(19)30127-3\n10.1016/j.ebr.2019.100343\n100343\nArticle\nGeneralized tonic–clonic seizures with post-ictal atrial fibrillation\nElnazeir Marwa a1 Badugu Pradeepthi b1 Narayanan Siddharth c Hussain Abid c Bhagat Riwaj N.M.N. a Jones Christopher M. c Holiday Victoria N. a Evans Miles S. a Palade Adriana E. [email protected]⁎ a Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA\nb Department of Medicine, University of Louisville, 501 East Broadway, Suite 100, Louisville, KY 40202, USA\nc Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA\n⁎ Corresponding author at: Department of Neurology, University of Louisville, 500 South Jackson Street, Louisville, KY 40202, USA. [email protected] Joint first authors.\n\n\n30 10 2019 \n2020 \n30 10 2019 \n13 10034313 8 2019 18 10 2019 27 10 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Convulsive seizures are known to cause severe cardiopulmonary changes and increased autonomic activity. Limited reports describe peri-ictal cardiac arrhythmias such as atrial fibrillation (AF) with generalized tonic–clonic seizures (GTCS). We present a unique case of a healthy 23-year-old male patient with new onset prolonged AF in the setting of new onset seizures, occurring on three independent occasions. Over two years, our patient had multiple hospitalizations for seizures with an electrocardiogram (ECG) diagnosis of AF made on three different occasions, occurring during his post-ictal state (all within 30 min of seizure onset). These seizures were never captured by electroencephalography (EEG) or witnessed by the medical staff, but were reported by family and/or reviewed on video provided by them. After his first GTCS, his AF persisted and was medically cardioverted. Two additional instances of AF after witnessed GTCS have been captured. After his second unprovoked seizure, an anti-seizure drug (ASD) was prescribed. A multi-disciplinary approach may be adopted to address comorbidities associated with seizures. Aggressive evaluation and treatment should be employed for newly diagnosed and refractory seizure patients associated with arrhythmias, in our case AF. Peri-ictal arrhythmias may be considered a potential marker for increased sudden unexpected death in epilepsy (SUDEP) risk.\n\nHighlights\n• Association of new onset post-ictal atrial fibrillation (AF) with new onset generalized tonic-clonic seizure (GTCS) is rare\n\n• Over a two year period, an overall healthy 23-year-old male was found to have three independent AF occurrences after GTCS\n\n• A multi-disciplinary approach and aggressive treatment with anti-seizure drugs may be adopted to address such events\n\n\n\nKeywords\nAtrial fibrillationSeizuresEpilepsyArrhythmiasEEGECGSUDEP\n==== Body\n1 Introduction\nConvulsive seizures are associated with severe changes in cardiopulmonary activity that can result in central apnea, severe bradycardia and transient asystole [1]. Cardiac rhythm abnormalities such as sinus tachycardia, sinus bradycardia, ictal asystole, ventricular tachycardia (VT), ventricular fibrillation (VF), atrioventricular (AV) nodal block, atrial flutter and atrial fibrillation (AF) can occur during the ictal- and post-ictal phases. Among these, sinus tachycardia was identified as the most common arrhythmia associated with the generalized tonic–clonic seizures (GTCS) [2]. AF, an independent risk factor for stroke and a leading cause of death, is the most prevalent arrhythmia in general and epilepsy populations, with its prevalence relatively higher in men [3] and in patients with temporal lobe epilepsy [4]. However, there are only a few cases in the literature that report AF during the ictal- or post-ictal state [5,6]. We present a unique case of an epilepsy patient having new onset transient AF after his generalized convulsions.\n\n2 Case\nA 23-year-old African-American male with new onset seizure was also found to have new onset transient AF in his postictal period. His past medical history was significant for asthma, obesity (BMI 33.1 kg/m2), and smoking (cigarettes, marijuana). His neurological examination, initial brain imaging, electroencephalography (EEG) and trans-thoracic echocardiogram (ECG) were unremarkable during his first admission for seizure. His first GTCS was at work, described by family as shaking all over, without reported tongue biting, or urinary/bowel incontinence. With unremarkable initial work-up, along with new onset of AF at that time, an initial diagnosis of convulsive syncope was made, with no anti-seizure drug (ASD) being initiated. Subsequent seizures consisted of psychomotor arrest, progressing to GTCS as reported by family/co-workers (patient denied any auras). Hospitalization during the post-ictal phase recorded AF with a rapid ventricular response (RVR) as recorded in the ECG (Fig. 1). Within two days, he spontaneously converted to normal sinus rhythm and was started on apixaban, diltiazem and metoprolol. Follow-up portable cardiac monitoring showed no evidence of recurrent arrhythmia. Beta-blocker and apixaban were discontinued due to symptomatic bradycardia, and respectively low CHA2DS2-VASc score. Multiple prior hospitalizations over a 5-year period for knee-related injuries included an ECG/cardiac monitoring, showing normal sinus rhythm.Fig. 1 AF after the initial GTCS episode. The above EKG demonstrates the AF observed within 30 min, after the initial GTCS episode (August 2017). The heart rate during this period was 116 BPM.\n\nFig. 1\n\nSix months later, levetiracetam was started after the second unprovoked GTCS and changed to valproic acid due to behavioral side effects. Poor compliance led to several admissions after sustaining seizures. During these encounters, multiple 24-hour EEG recording showed mild background slowing and no seizure activity after the anti-seizure medication load. Subsequent brain MRI showed mild asymmetry of hippocampi with no abnormality in the temporal lobes.Fig. 2 EEG during EMU admission (Feb 2019). The EEG of the patient, (A) at the beginning of the seizure episode (the top arrow shows left temporal moderate rhythmic theta activity), and (B) at the end of the seizure (one-minute duration). The heart rate (green), was consistent during episode. The patient did not progress to a GTCS. The two images are at sensitivity 10.\n\nFig. 2\n\nFourteen months after the first seizure, the patient was brought to the emergency department with a prolonged seizure, lasting over 5 min, when the second prolonged AF with RVR was identified. A third seizure associated with AF and RVR prompting hospitalization was captured by family on video and consisted of confusion, right arm tonic posturing, forced head deviation to the right, and progression to a GTCS. A follow-up epilepsy monitoring unit (EMU) recording to determine seizure localization prompting anti-seizure medication discontinuation, captured one focal seizure with left temporal onset and psychomotor arrest but no changes in the cardiac rate or rhythm (Fig. 2). As per EMU protocol, he was immediately treated with lorazepam to avoid secondary generalization and to prevent sudden unexpected death in epilepsy (SUDEP). At this time the patient realized the importance of medication compliance and his epilepsy is currently well controlled with two ASDs.\n\n3 Discussion\nIn convulsive seizures, there is an increased sympathetic activity that is reflected as a peak in catecholamine and electrodermal activity [7]. During the post-ictal state following GTCS, there is an autonomic dysregulation with increased sympathetic and decreased parasympathetic outflow. This may generate fatal arrhythmias and potential SUDEP [7,8]. In addition, the association between arrhythmias and seizures could be due to the direct stimulation of the central autonomic centers [2,9,10]. Seizures originating from the amygdala, hippocampus, insular cortex, and the frontotemporal regions can produce a wide range of cardiac abnormalities [11,12] with studies suggesting that the insular cortex has a direct influence on the cardiac rate and rhythm [4,11]. We observed that our patient had a past history of hypertension and obesity. Cardiovascular comorbidities and their associated risk factors are more common in adults with chronic epilepsy [2,13], particularly those who have a higher incidence of hypertension and obesity. Several of these factors pose a risk towards the development of stroke.\n\nFatal arrhythmias and ECG abnormalities are more likely to be observed during or after a generalized seizure and with prolonged convulsive activity [9,10]. Studies indicate that ictal asystole, VT and VF are associated with SUDEP [7]. Concerns have been expressed over AF compromising ventricular output, and thus could be a precipitating factor for SUDEP [6]. There are very few reports showing post-ictal AF diagnosed during video-EEG monitoring [14]. A study reported a past medical history of AF in two patients with SUDEP but ictal or immediate post-ictal ECG recording in these patients were not available [15]. Clinical evidence showing association between AF and SUDEP is scant and it has been suggested that peri-ictal arrhythmias should be considered as a marker for increased SUDEP risk [7].\n\nWe report three instances of new onset and transient postictal AF after GTCS in our patient, occurring over a period of 24 months. Between his first and second AF associated with seizures events described above, the patient had multiple other seizures prompting five additional ER evaluations or ICU hospitalizations during which AF was not demonstrated on ECG. None of his GTCS occurred while in the hospital, therefore the exact timing of onset of AF in relation to the ictal onset cannot be quantified. It has been hypothesized that following GTCS, there is a period of severe autonomic dysregulation strongly characterized by excessive sympathetic activation in tandem with parasympathetic suppression in the early post-ictal phase; the later phase seems to be dominated by impaired vagal recovery. AF can induce cardiac failure with severe hemodynamic repercussions, and it is a well-known cause of stroke. To our knowledge, a single prior report was published showing post-ictal AF/flutter lasting just minutes as a marker for SUDEP [14]. We considered our patient to have a much higher risk of stroke and/or SUDEP, due to prolonged post-ictal AF, lasting over two days. The post-ictal AF connected with the GTCS presented as an RVR, hence it was important to maintain the sinus rhythm and prevent peripheral embolization [14]. It is worthwhile considering whether or not post-ictal AF needs to be treated, since seizure control in itself is likely to prevent this arrhythmia. An extensive cardiac work-up is vital in these patients to differentiate between peri-ictal AF related to GTCS and those unrelated to seizures. If at all, the risk of SUDEP is unclear, because AF is considered a low-mortality arrhythmia, an implantable cardioverter-defibrillator is not generally indicated, although each case must be individually assessed. A 24-hour Holter ECG is essential to exclude intrinsic cardiac abnormalities [4,11]. Simultaneous video EEG and ECG recordings can establish the relationship between the seizure and the arrhythmia [15].\n\nPatients with AF are at the risk of stroke and systemic embolism without anticoagulant therapy. Seizure control is paramount in all patients, especially if associated with peri-ictal cardiac rhythm abnormalities. ASD selection plays an important role in the patients with intrinsic cardiac conductive tissue dysfunction. Lamotrigine, valproate and gabapentin have a minimal effect on the cardiac function whereas carbamazepine, phenytoin, barbiturates and benzodiazepines are linked with conduction abnormalities [4]. It is vital to closely monitor patients having post-ictal AF after seizures, with primary focus being given to the seizure control. Our patient had a low CHA2DS2-VASc score, therefore the anticoagulation therapy was discontinued. In general, a patient with a high CHA2DS2-VASc score requires anticoagulation therapy. Patients with history of ASD non-compliance or with refractory seizures, that are prescribed anticoagulation therapy, are at risk for prolonged or severe bleeding, especially if they sustain injuries during seizures. Hence, it is important to choose an ASD medication with good efficacy and minimal drug-to-drug interaction and an anticoagulant that can be quickly reversed.\n\n4 Conclusions\nPost-ictal AF, though rarely reported, is a highly dangerous seizure complication. GTCS associated with prolonged arrhythmias such as AF can complicate the healthcare management in patients. AF, when linked with GTCS, has been associated with post-ictal generalized EEG suppression and autonomic dysregulation, and can be potentially connected to SUDEP [14]. A multi-disciplinary approach should be an integral part of AF management if related to seizures, in order to prevent stroke. Aggressive control of the seizures can prevent post-ictal AF occurrence.\n\nThe following is the supplementary data related to this article.Video 1\nThe seizure episode of patient captured by family when the third AF was identified.\n\nVideo 1 \n\nAuthorship of the paper\nP.B., M.E., S.N., and A.P. collected and analyzed the literature, and wrote the manuscript. P.B., M.E., A.H., S.N., and R.B. analyzed the literature. C.J., V.H., M.E., and A.P. reviewed and edited the manuscript. All authors read and agreed to the final version of the manuscript.\n\nEthical statement\nAs referenced by Epilepsy and Behavior Case Reports, all authors report that they have conformed to the principles of ethics in publishing and ethical guidelines for journal publication. Patient consent is provided.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to disclose related to this manuscript.\n==== Refs\nReferences\n1 Ryvlin P. Nashef L. Lhatoo S.D. Bateman L.M. Bird J. Bleasel A. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study Lancet Neurol 12 10 2013 966 977 24012372 \n2 Shmuely S. van der Lende M. Lamberts R.J. Sander J.W. Thijs R.D. The heart of epilepsy: current views and future concepts Seizure 44 2017 176 183 27843098 \n3 Desai R. Rupareliya C. Patel U. Naqvi S. Patel S. Lunagariya A. Burden of arrhythmias in epilepsy patients: a nationwide inpatient analysis of 1.4 million hospitalizations in the United States Cureus 9 8 2017 e1550 29018647 \n4 Lim E.C. Lim S.H. Wilder-Smith E. Brain seizes, heart ceases: a case of ictal asystole J Neurol Neurosurg Psychiatry 69 4 2000 557 559 10990526 \n5 Basili L.M. Morano A. Fattouch J. Fanella M. Albini M. Avorio F. Ictal atrial fibrillation during focal seizures: a case report and literature review Epileptic Disord 21 3 2019 295 301 31225804 \n6 Surges R. Moskau S. Viebahn B. Schoene-Bake J. Schwab J. Elger C. Prolonged atrial fibrillation following generalized tonic–clonic seizures Seizure - European Journal of Epilepsy 21 8 2012 643 645 22698381 \n7 van der Lende M. Surges R. Sander J.W. Thijs R.D. Cardiac arrhythmias during or after epileptic seizures J Neurol Neurosurg Psychiatry 87 1 2016 69 26038597 \n8 Poh M.Z. Loddenkemper T. Reinsberger C. Swenson N.C. Goyal S. Madsen J.R. Autonomic changes with seizures correlate with postictal EEG suppression Neurology 78 23 2012 1868 1876 22539579 \n9 Nei M. Ho R.T. Sperling M.R. EKG abnormalities during partial seizures in refractory epilepsy Epilepsia 41 5 2000 542 548 10802759 \n10 Devinsky O. Effects of seizures on autonomic and cardiovascular function Epilepsy Curr 4 2 2004 43 46 15562299 \n11 Kishk N. Nawito A. El-Damaty A. Ragab A. Ictal asystole: a case presentation BMC Neurol 18 1 2018 100 30031379 \n12 Schernthaner C. Lindinger G. Potzelberger K. Zeiler K. Baumgartner C. Autonomic epilepsy—the influence of epileptic discharges on heart rate and rhythm Wien Klin Wochenschr 111 10 1999 392 401 10413832 \n13 Kadima N. K. R. Z. M. Helmers S. Comorbidity in adults with epilepsy—United States, 2010 Center for Disease Control and Prevention MMWR 62 2013 849 853 24172878 \n14 Sanchez-Larsen A. Aznar-Lain G. Benito B. Principe A. Ley M. Tauste Campo A. Post-ictal atrial fibrillation detected during video-EEG monitoring: case report, proposed physiopathologic mechanism and therapeutic considerations Epilepsy Behav Case Rep 8 2017 40 43 28856096 \n15 Nei M. Ho R.T. Abou-Khalil B.W. Drislane F.W. Liporace J. Romeo A. EEG and ECG in sudden unexplained death in epilepsy Epilepsia 45 4 2004 338 345 15030496\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2589-9864", "issue": "13()", "journal": "Epilepsy & behavior reports", "keywords": "Arrhythmias; Atrial fibrillation; ECG; EEG; Epilepsy; SUDEP; Seizures", "medline_ta": "Epilepsy Behav Rep", "mesh_terms": null, "nlm_unique_id": "101750909", "other_id": null, "pages": "100343", "pmc": null, "pmid": "32322817", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "27843098;22539579;30031379;28856096;24172878;10990526;26038597;15030496;15562299;31225804;24012372;10802759;29018647;10413832;22698381", "title": "Generalized tonic-clonic seizures with post-ictal atrial fibrillation.", "title_normalized": "generalized tonic clonic seizures with post ictal atrial fibrillation" }

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"patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Behaviour disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "CHA2DS2-VASc annual stroke risk low", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ELNAZEIR M, BADUGU P, NARAYANAN S, HUSSAIN A, BHAGAT RNMN, JONES CM ET AL. GENERALIZED TONIC-CLONIC SEIZURES WITH POST-ICTAL ATRIAL FIBRILLATION. EPILEPSY AND BEHAVIOR REPORTS. 2020?13:ARTICLE NUMBER 100343. DOI: 10.1016/J.EBR.2019.100343.", "literaturereference_normalized": "generalized tonic clonic seizures with post ictal atrial fibrillation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200422", "receivedate": "20200212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17405272, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]

{ "abstract": "BACKGROUND\nThe aim of this study is to determine the incidence, etiology, clinical characteristics, and outcomes of renal transplant recipients diagnosed and treated for central nervous system (CNS) infection at our institution.\n\n\nMETHODS\nWe analyzed data from all renal transplant recipients between January 2007 and December 2019 that were diagnosed and treated for CNS infections at our institution.\n\n\nRESULTS\nOf 1374 patients who received renal allografts, 13 were diagnosed with CNS infections (9 males), with a mean age of 53.5 years. Patients were diagnosed with CNS infections between 2 months and 11 years after the transplantation. Causative agents included JC virus, Streptococcus pneumoniae, Cryptococcus neoformans, Herpes zoster virus, Mycobacterium tuberculosis, Listeria monocytogenes, and West Nile virus. One patient had concomitant Nocardia and Neisseria infection. Immunosuppression was reduced in all patients. The patient with JC encephalitis and the patient with concomitant Neisseria and Nocardia meningitis died. One patient was returned to dialysis. Other patients recovered with differing levels of neurologic sequelae.\n\n\nCONCLUSIONS\nCentral nervous system infections in renal transplant recipients are rare. However, they are associated with significant morbidity and mortality. A high level of awareness is needed: neurological symptoms may be nonspecific and caused by non-infectious conditions related to the underlying disease, or side-effects of immunosuppressive drugs.", "affiliations": "Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.", "authors": "Basic-Jukic|Nikolina|N|https://orcid.org/0000-0002-0221-2758;Juric|Ivana|I|;Furic-Cunko|Vesna|V|;Kastelan|Zeljko|Z|", "chemical_list": null, "country": "Denmark", "delete": false, "doi": "10.1111/tid.13341", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "22(4)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "CNS infection; cryptococcus", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D020806:Central Nervous System Bacterial Infections; D002494:Central Nervous System Infections; D020805:Central Nervous System Viral Diseases; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D066027:Transplant Recipients", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13341", "pmc": null, "pmid": "32453874", "pubdate": "2020-08", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Central nervous system infections in renal transplant recipients.", "title_normalized": "central nervous system infections in renal transplant recipients" }

[ { "companynumb": "HR-TEVA-2020-HR-1843713", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis pneumococcal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201029", "receivedate": "20201029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18440512, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "HR-TEVA-2020-HR-1843703", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tuberculosis of central nervous system", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Tuberculosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201030", "receivedate": "20201030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18445742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "HR-TEVA-2020-HR-1843714", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis pneumococcal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201029", "receivedate": "20201029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18440595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "HR-TEVA-2020-HR-1843716", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningococcal infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Encephalitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nocardiosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BASIC-JUKIC N, JURIC I, FURIC-CUNKO V, KASTELAN Z. CENTRAL NERVOUS SYSTEM INFECTIONS IN RENAL TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2020?22(4):E13341.", "literaturereference_normalized": "central nervous system infections in renal transplant recipients", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20201029", "receivedate": "20201029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18440511, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]

{ "abstract": "BACKGROUND\nThe outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated.\n\n\nOBJECTIVE\nTo assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC.\n\n\nMETHODS\nThis was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis.\n\n\nRESULTS\nSeventy-nine patients were included. Fifty-four patients (68.4%) achieved short-term clinical response and 41 patients (51.9%) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8-26], 33 patients (41.8%) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.12-0.49; p < 0.001]. During a median follow-up of 24 months (IQR 13-34), 9 patients (11.4%) needed colectomy. Short-term response was identified as a predictor of colectomy avoidance (HR 0.14; 95% CI 0.03-0.69; p < 0.007).\n\n\nCONCLUSIONS\nIn UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70% of patients. In the long term, 58% of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86% reduction in the relative risk of colectomy.", "affiliations": "Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Clínico de Santiago, Santiago de Compostela, Spain. [email protected].;Department of Gastroenterology, Hospital Puerta de Hierro, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital de Cabueñes, Gijón, Spain. [email protected].;Department of Gastroenterology, Hospital La Fe, Valencia, Spain. [email protected].;Department of Gastroenterology, Hospital La Paz, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Reina Sofía and IMIBIC, Universidad de Córdoba, Córdoba, Spain. [email protected].;Department of Gastroenterology, Hospital Gregorio Marañón, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital de Fuenlabrada, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Infanta Leonor, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Infanta Sofía, Madrid, Spain. [email protected].;Department of Gastroenterology, Hospital Gregorio Marañón, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Clínico San Carlos, c/Profesor Martín Lagos s/n, 28040, Madrid, Spain. [email protected].;Inflammatory Bowel Disease Unit, Hospital Universitario Moncloa, Madrid, Spain. [email protected].", "authors": "Taxonera|Carlos|C|;Barreiro-de Acosta|Manuel|M|;Calvo|Marta|M|;Saro|Cristina|C|;Bastida|Guillermo|G|;Martín-Arranz|María D|MD|;Gisbert|Javier P|JP|;García-Sánchez|Valle|V|;Marín-Jiménez|Ignacio|I|;Bermejo|Fernando|F|;Chaparro|María|M|;Ponferrada|Ángel|Á|;Martínez-Montiel|María P|MP|;Pajares|Ramón|R|;de Gracia|Celia|C|;Olivares|David|D|;Alba|Cristina|C|;Mendoza|Juan L|JL|;Fernández-Blanco|Ignacio|I|", "chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab", "country": "United States", "delete": false, "doi": "10.1007/s10620-015-3735-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-2116", "issue": "60(10)", "journal": "Digestive diseases and sciences", "keywords": "Cohort study; Colectomy; Dose escalation; Dose optimization; Infliximab; Ulcerative colitis", "medline_ta": "Dig Dis Sci", "mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003082:Colectomy; D003093:Colitis, Ulcerative; D016001:Confidence Intervals; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "7902782", "other_id": null, "pages": "3075-84", "pmc": null, "pmid": "26044830", "pubdate": "2015-10", "publication_types": "D003160:Comparative Study; D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study", "references": "21122530;22860894;24512909;24758588;16151544;21172214;21133961;23964932;14762776;25989340;25389599;16339095;25083091;19174781;21484965;25117777;24013361;19596014;24121042;20736936;24246151;21466486;22239070;24690137;19651627;21045814;22294554;22062358;23770005", "title": "Infliximab Dose Escalation as an Effective Strategy for Managing Secondary Loss of Response in Ulcerative Colitis.", "title_normalized": "infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis" }

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"actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Colectomy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse drug reaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral thrombosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psoriasis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prostate cancer", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure before pregnancy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAXONERA C, ACOSTA MB, CALVO M, SARO C, BASTIDA G, MARTY N-ARRANZ M, ET AL. INFLIXIMAB DOSE ESCALATION AS AN EFFECTIVE STRATEGY FOR MANAGING SECONDARY LOSS OF RESPONSE IN ULCERATIVE COLITIS. DIG DIS SCI 2015?60 (10):3075-3084.", "literaturereference_normalized": "infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20151016", "receivedate": "20151005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11593919, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "Systemic drug exposure can produce a skin reaction consisting of symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) occurs after systemic exposure to a drug in which the patient was not previously sensitised, either in the first dose or after several doses. The mechanism of SDRIFE is unknown but is hypothesised to be the result of a delayed hypersensitivity response resulting in a cutaneous eruption some days after the exposure to the drug. The diagnosis should be clinical, based on the history and examination, but skin tests can also be performed to confirm sensitisation. But, as always, the gold-standard test is oral provocation. It is important to know this clinical entity to prevent re-exposure to the responsible allergen in the future.", "affiliations": "Allergy Department, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.;Allergy Department, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.;Allergy Department, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.;Nursing Department, Hospital Universitario Nuestra Senora de la Candelaria, Santa Cruz de Tenerife, Spain.", "authors": "Cabrera Hernandez|Virginia|V|;Gonzalez Afonso|Monica|M|;Callero Viera|Ariel|A|http://orcid.org/0000-0002-8964-8262;Martin-Fernandez Martin|Lidon|L|", "chemical_list": "D013256:Steroids; D002981:Clindamycin", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-230077", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(8)", "journal": "BMJ case reports", "keywords": "dermatology; skin; unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000284:Administration, Oral; D001706:Biopsy; D002981:Clindamycin; D003875:Drug Eruptions; D005076:Exanthema; D005260:Female; D006801:Humans; D007402:Intertrigo; D008875:Middle Aged; D013256:Steroids; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31377719", "pubdate": "2019-08-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15606657;30062790;21659857;24001419;25932057;21469762;21469764", "title": "Symmetrical drug-related intertriginous and flexural exanthema due to clindamycin.", "title_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin" }

[ { "companynumb": "ES-BAUSCH-BL-2019-024763", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "050782", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "8", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ V, GONZALEZ AFONSO M, CALLERO VIERA A, MARTIN-FERNANDEZ MARTIN L. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. BMJ CASE REPORTS.. 2019?12(8):. DOI:10.1136/BCR-2019-230077", "literaturereference_normalized": "symmetrical drug related intertriginous and flexural exanthema due to clindamycin", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190830", "receivedate": "20190830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16761328, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "ES-PFIZER INC-2019369364", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "050162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "150 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Symmetrical drug-related intertriginous and flexural exanthema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CABRERA HERNANDEZ, V.. SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. 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SYMMETRICAL DRUG-RELATED INTERTRIGINOUS AND FLEXURAL EXANTHEMA DUE TO CLINDAMYCIN. 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{ "abstract": "Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.", "affiliations": "Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA. [email protected].;Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA.;Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA.;Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA.;Boehringer Ingelheim International GmbH, Biberach, Germany.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.;Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.", "authors": "Cortes|Jorge|J|;Podoltsev|Nikolai|N|;Kantarjian|Hagop|H|;Borthakur|Gautam|G|;Zeidan|Amer M|AM|;Stahl|Maximilian|M|;Taube|Tillmann|T|;Fagan|Nora|N|;Rajeswari|Sushmita|S|;Uy|Geoffrey L|GL|", "chemical_list": "C541363:BI 6727; D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000077209:Decitabine; D017346:Protein Serine-Threonine Kinases; C090134:polo-like kinase 1", "country": "Japan", "delete": false, "doi": "10.1007/s12185-020-02994-8", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "113(1)", "journal": "International journal of hematology", "keywords": "AML; Decitabine; PLK1; Phase 1; Volasertib", "medline_ta": "Int J Hematol", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018797:Cell Cycle Proteins; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D064147:Febrile Neutropenia; D001068:Feeding and Eating Disorders; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D058990:Molecular Targeted Therapy; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D016896:Treatment Outcome", "nlm_unique_id": "9111627", "other_id": null, "pages": "92-99", "pmc": null, "pmid": "32951163", "pubdate": "2021-01", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": "24033250;24520204", "title": "Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia.", "title_normalized": "phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia" }

[ { "companynumb": "US-OTSUKA-2020_023610", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VOLASERTIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "350 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "350", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOLASERTIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DECITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021790", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MG/M2, DAYS 1?5", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DECITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VOLASERTIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOLASERTIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VOLASERTIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE MYELOID LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VOLASERTIB" } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Myelosuppression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CORTES J, PODOLTSEV N, KANTARJIAN H, BORTHAKUR G, ZEIDAN AM, STAHL M ET AL. PHASE 1 DOSE ESCALATION TRIAL OF VOLASERTIB IN COMBINATION WITH DECITABINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA. INT J HEMATOL. 2021?113 (1):92?9", "literaturereference_normalized": "phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210405", "receivedate": "20201001", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18335764, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Because antithymocyte globulin (ATG) is increasingly used to prevent graft-versus-host disease (GVHD), we performed a retrospective study in adult patients transplanted at our center between January 2008 and December 2012 to explore incidence, characteristics, potential risk factors, and consequences of severe acute hepatotoxicity (SAH) of rabbit ATG (Thymoglobulin) defined as a grade 3 to 4 increase of transaminases. Two hundred twelve patients were included. SAH was diagnosed in 55 patients, representing an incidence of 26%. SAH occurred at a median time of 2 days (range, 1 to 3) after ATG administration, reaching maximum median levels of aspartate aminotransferase and alanine aminotransferase of 8.7 × upper limit of normal (ULN; range, 1.2 to 160) and 11.7 × ULN (range, 4-100), respectively. The International Normalized Ratio was beyond the normal range in 44% of patients. Transaminases decreased below 2 × ULN after a median time of 9 days. We do not report any deleterious impact of SAH on survival, nonrelapse mortality, relapse, or GVHD. Blood systolic pressure < 90 mm Hg during administration of ATG and 2 previous autologous SCT were identified as risk factors for SAH. We believe physicians should be aware of this common toxicity immediately after the administration of ATG to avoid any potential hepatotoxic drug before the resolution and to prevent any risk of hemorrhagic accident.", "affiliations": "Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France. Electronic address: [email protected].;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France.;Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.", "authors": "Médiavilla|Clémence|C|;Vigouroux|Stéphane|S|;Tabrizi|Reza|R|;Pigneux|Arnaud|A|;Duclos|Cédric|C|;Mohr|Catherine|C|;Robles|Margot|M|;Milpied|Noël|N|", "chemical_list": "D000961:Antilymphocyte Serum; C512542:thymoglobulin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "21(4)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Allogeneic stem cell transplantation; Antithymocyte globulin; Grades 3 to 4 hepatitis", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D064591:Allografts; D000818:Animals; D000961:Antilymphocyte Serum; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D006505:Hepatitis; D006801:Humans; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D015996:Survival Rate", "nlm_unique_id": "9600628", "other_id": null, "pages": "661-5", "pmc": null, "pmid": "25536216", "pubdate": "2015-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin (thymoglobulin) administered before allogeneic stem cell transplantation.", "title_normalized": "transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin thymoglobulin administered before allogeneic stem cell transplantation" }

[ { "companynumb": "FR-SA-2015SA027262", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".8", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSULFAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "103869", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THYMOGLOBULIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PREMEDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODEOXYCHOLIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LESS THAN 4G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXCHLORPHENIRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PREMEDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXCHLORPHENIRAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100UI/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MEDIAVILLA C, VIGOUROUX S, TABRIZI R, PIGNEUX A, DUCLOS C, MOHR C ET AL. TRANSIENT GRADES 3 TO 4 ACUTE HEPATITIS IS A COMMON COMPLICATION OF RABBIT ANTITHYMOCYTE GLOBULIN (THYMOGLOBULIN) ADMINISTERED BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION. BIOL. BLOOD MARROW TRANSPLANT; 2014 OCT 12. 2015;21:661-65. DOI: 10.1016/J.BBMT.2014.12.014.", "literaturereference_normalized": "transient grades 3 to 4 acute hepatitis is a common complication of rabbit antithymocyte globulin thymoglobulin administered before allogeneic stem cell transplantation", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20150320", "receivedate": "20150309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10897316, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "BACKGROUND Pituitary metastasis is uncommon, breast and lung cancers being the most frequent primary tumors. Renal cell carcinoma (RCC) is a rare cause of pituitary metastases, with only a few cases described to date. CASE REPORT We report a case of a 61-year-old man who presented with a progressive deterioration of visual acuity and field associated with a bitemporal hemianopsia. Two years ago, he underwent radical right nephrectomy for a clear cell RCC (ccRCC). The biological tests showed pan-hypopituitarism and diabetes insipidus. Brain MRI revealed a large sellar tumor lesion bilaterally infiltrating the cavernous sinuses, which was surgically resected. Histology confirmed a ccRCC pituitary metastasis. The patient received post-surgical radiotherapy. Considering the presence of concomitant extra-pituitary metastases, treatment with sunitinib was started, followed by several lines of therapy with axitinib, everolimus, and sorafenib because of tumor progression. The patient also presented with a pituitary tumor recurrence, which was treated by stereotaxic radiotherapy. He died five years after the initial diagnosis of RCC and 30 months after the diagnosis of the pituitary metastasis. CONCLUSIONS There are no standardized treatment guidelines for management of pituitary metastases. Pituitary surgery plays a role in symptom palliation, and it does not have any relevant impact on survival. Exclusive radiotherapy or stereotaxic radiotherapy could be an alternative to surgery in patients whose general condition is poor or who have concomitant extra-pituitary metastases.", "affiliations": "Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Radiology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Radiotherapy, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.;Division of Medical Oncology, Regional Hospital Center (CHR) Metz-Thionville, Ars-Laquenexy, France.", "authors": "Wendel|Chloé|C|;Campitiello|Marco|M|;Plastino|Francesca|F|;Eid|Nada|N|;Hennequin|Laurent|L|;Quétin|Philippe|P|;Longo|Raffaele|R|", "chemical_list": "D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib", "country": "United States", "delete": false, "doi": "10.12659/ajcr.901032", "fulltext": null, "fulltext_license": null, "issn_linking": "1941-5923", "issue": "18()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000077784:Axitinib; D002292:Carcinoma, Renal Cell; D018450:Disease Progression; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019635:Neurosurgical Procedures; D009536:Niacinamide; D010671:Phenylurea Compounds; D010911:Pituitary Neoplasms; D011758:Pyrroles; D018714:Radiotherapy, Adjuvant; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome", "nlm_unique_id": "101489566", "other_id": null, "pages": "7-11", "pmc": null, "pmid": "28044054", "pubdate": "2017-01-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "4355105;1395423;20694412;14959938;22480977;9647174;24445565;22500201;17541748;22990000;21421711;14764764;24175029;26514360", "title": "Pituitary Metastasis from Renal Cell Carcinoma: Description of a Case Report.", "title_normalized": "pituitary metastasis from renal cell carcinoma description of a case report" }

[ { "companynumb": "PHHY2017FR019187", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLEAR CELL RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201503", "drugenddateformat": "610", "drugindication": "CLEAR CELL RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201412", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to spine", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to pituitary gland", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to the respiratory system", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WENDEL C, CAMPITIELLO M, PLASTINO F, EID N, HENNEQUIN L, QUETIN P ET AL.. PITUITARY METASTASIS FROM RENAL CELL CARCINOMA: DESCRIPTION OF A CASE REPORT. AMERICAN JOURNAL OF CASE REPORTS. 2017;18:7-11", "literaturereference_normalized": "pituitary metastasis from renal cell carcinoma description of a case report", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20170212", "receivedate": "20170212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13224428, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "Hyperkalaemia is a potentially life-threatening condition frequently encountered in hospitalised patients. Among the many causes of hyperkalaemia, drugs have often been implicated. In the South African context, with the high burden of HIV, there is an increased incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), and consequently many patients receive high doses of trimethoprim-sulfamethoxazole. A lesser-known side-effect of the trimethoprim component of this combination antibiotic is hyperkalaemia. We report a case in which life-threatening hyperkalaemia developed after institution of high-dose co-trimoxazole for PJP.", "affiliations": "Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. [email protected].", "authors": "Du Plooy|N|N|;Rayner|B|B|", "chemical_list": "D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim", "country": "South Africa", "delete": false, "doi": "10.7196/SAMJ.2019.v109i2.13660", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "109(2)", "journal": "South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde", "keywords": null, "medline_ta": "S Afr Med J", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000900:Anti-Bacterial Agents; D005260:Female; D015658:HIV Infections; D006801:Humans; D006947:Hyperkalemia; D008875:Middle Aged; D011020:Pneumonia, Pneumocystis; D014295:Trimethoprim; D015662:Trimethoprim, Sulfamethoxazole Drug Combination", "nlm_unique_id": "0404520", "other_id": null, "pages": "89-90", "pmc": null, "pmid": "30834857", "pubdate": "2019-01-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Life-threatening hyperkalaemia due to trimethoprim in a patient treated for Pneumocystis jirovecii pneumonia.", "title_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia" }

[ { "companynumb": "ZA-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-204366", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "017377", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "(1600 MG/320MG), QID (6-HOURLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prerenal failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DU PLOOY N, RAYNER B. LIFE-THREATENING HYPERKALAEMIA DUE TO TRIMETHOPRIM IN A PATIENT TREATED FOR PNEUMOCYSTIS JIROVECII PNEUMONIA. S AFR MED J. 2019?109(2):89-90", "literaturereference_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia", "qualification": "3", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20190812", "receivedate": "20190812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16691797, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "ZA-SA-2019SA071024", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1600/320 MG, Q6H", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PRIMAQUINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008316", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRIMAQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prerenal failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "DU PLOOY N, RAYNER B.. LIFE-THREATENING HYPERKALAEMIA DUE TO TRIMETHOPRIM IN A PATIENT TREATED FOR PNEUMOCYSTIS JIROVECII PNEUMONIA.. S AFR MED J.. 2019?109(2):89-90", "literaturereference_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia", "qualification": "1", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20190319", "receivedate": "20190318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16084505, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "NVSC2019ZA086795", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM GLUCONATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021163", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERKALAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM GLUCONATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (1600 MG/320 MG 6-HOURLY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETOXAZOL/TRIMETOPRIM" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PLOOY ND, RAYNER B. LIFE-THREATENING HYPERKALAEMIA DUE TO TRIMETHOPRIM IN A PATIENT TREATED FOR PNEUMOCYSTIS JIROVECII PNEUMONIA. SOUTH AFRICAN MEDICAL JOURNAL. 2019?109(2):89-90", "literaturereference_normalized": "life threatening hyperkalaemia due to trimethoprim in a patient treated for pneumocystis jirovecii pneumonia", "qualification": "3", "reportercountry": "ZA" }, "primarysourcecountry": "ZA", "receiptdate": "20200129", "receivedate": "20200129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17343915, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "Primary biliary cirrhosis (PBC) and multiple sclerosis (MS) are considered autoimmune diseases with a multifactorial aetiology which is thought to be due to a combination of genetic predisposition and environmental triggers. An association of both diseases has been previously described in sporadic case reports. Fingolimod, an antagonist of the sphingosine 1 phosphate receptor family (S1P1/3/4/5), is a promising and effective drug in the treatment of MS. Here we describe a case of PBC like syndrome that was unmasked, concomitantly or consequently to Epstein Barr virus (EBV) infection reactivation, in a 34 year old male patient with relapsing remitting multiple sclerosis who was receiving fingolimod treatment.", "affiliations": "Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi and A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.;Internal Medicine and Hepatology, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences; Department of Clinical and Experimental Medicine and Surgery F. Magrassi e A. Lanzara; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples (SUN); Internal Medicine of Clinic Hospital of Marcianise, Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Caserta, Italy.", "authors": "Marrone|Aldo|A|;Signoriello|Elisabetta|E|;Alfieri|Gennaro|G|;Dalla Mora|Liliana|L|;Rinaldi|Luca|L|;Rainone|Ilaria|I|;Adinolfi|Luigi Elio|LE|;Lus|Giacomo|G|", "chemical_list": "D002756:Cholagogues and Choleretics; D007166:Immunosuppressive Agents; D014580:Ursodeoxycholic Acid; D000068876:Fingolimod Hydrochloride", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1124-9390", "issue": "22(4)", "journal": "Le infezioni in medicina", "keywords": null, "medline_ta": "Infez Med", "mesh_terms": "D000328:Adult; D002756:Cholagogues and Choleretics; D020031:Epstein-Barr Virus Infections; D000068876:Fingolimod Hydrochloride; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008105:Liver Cirrhosis, Biliary; D008297:Male; D009103:Multiple Sclerosis; D012008:Recurrence; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid; D028761:Withholding Treatment", "nlm_unique_id": "9613961", "other_id": null, "pages": "331-6", "pmc": null, "pmid": "25551852", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epstein Barr virus infection reactivation as a possible trigger of primary biliary cirrhosis-like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment.", "title_normalized": "epstein barr virus infection reactivation as a possible trigger of primary biliary cirrhosis like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment" }

[ { "companynumb": "PHHY2015IT001112", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FINGOLIMOD HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022527", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "0.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILENYA" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphadenopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic steatosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal discomfort", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatomegaly", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Biliary cirrhosis primary", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARRONE A, SIGNORIELLO E, ALFIERI G, DALLA MORA L, RINALDI L, RAINONE I,ETC,.,. EPSTEIN BARR VIRUS INFECTION REACTIVATION AS A POSSIBLE TRIGGER OF PRIMARY BILIARY CIRRHOSIS-LIKE SYNDROME IN A PATIENT WITH MULTIPLE SCLEROSIS IN THE COURSE OF FINGOLIMOD TREATMENT. INFEZ MED. 2014;22 (4):331-336", "literaturereference_normalized": "epstein barr virus infection reactivation as a possible trigger of primary biliary cirrhosis like syndrome in a patient with multiple sclerosis in the course of fingolimod treatment", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20150116", "receivedate": "20150116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10716342, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "OBJECTIVE\nTo analyze our results with mycophenolate mofetil (MMF) in stable liver transplantation (LT) patients presenting with adverse events (AE) related to prolonged use of calcineurin inhibitors (CNI).\n\n\nMETHODS\nConversion to MMF was performed in 56 out of 323 LT patients from 91-02: 24 (43%) were converted to MMF in monotherapy and 32 (57%) to MMF+low doses of CNI. The indication for conversion was chronic renal insufficiency (CRI) in all patients. The mean time between AE and conversion was 38.7+/-30 months (r: 2-101 m). Post-conversion follow-up was 39+/-20 months (r: 3-72 m).\n\n\nRESULTS\nThe calculated creatinine clearance (Crauckoft), improved significantly in all patients. In those converted to MMF, improvement was seen during the first 18 months for urea and during the first 6 months for creatinine. In patients converted to MMF+CNI, improvement was maintained throughout the conversion period for both urea and creatinine. Eleven (19.6%) patients underwent acute rejection (2 severe episodes in the MMF group and 1 death). Hypertension was present in 31 patients but only improved in 4 (7%). Dyslipemia was found in 12 and improved in 4 (7%). DM was present in 14 and improved in 1 (2%).\n\n\nCONCLUSIONS\nConversion to MMF in monotherapy is useful in stable LT patients with CRI due to CNI, although this result is offset by more severe rejections. Therefore, for AE secondary to CNI, we propose an early conversion to MMF+low doses of CNI as a first step. If liver function remains stable and AEs persist or progress, conversion to MMF in monotherapy is recommended, as a second step, with close monitoring of the patient.", "affiliations": "Liver Transplantation Unit of the Department of General Surgery, Hospital Vall Hebrón, Universidad Autónoma Barcelona, Spain. [email protected] <[email protected]>", "authors": "Bilbao|Itxarone|I|;Castells|Luis|L|;Rojas|Luis|L|;Cancino|Jorge|J|;Dopazo|Cristina|C|;Castro|Ernest|E|;Pou|Leonor|L|;Andino|Ricardo|R|;Margarit|Carlos|C|", "chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D014508:Urea; D003404:Creatinine; D009173:Mycophenolic Acid", "country": "Netherlands", "delete": false, "doi": "10.1016/j.intimp.2006.09.022", "fulltext": null, "fulltext_license": null, "issn_linking": "1567-5769", "issue": "6(13-14)", "journal": "International immunopharmacology", "keywords": null, "medline_ta": "Int Immunopharmacol", "mesh_terms": "D000368:Aged; D065095:Calcineurin Inhibitors; D003404:Creatinine; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006801:Humans; D006973:Hypertension; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007668:Kidney; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011183:Postoperative Complications; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014508:Urea", "nlm_unique_id": "100965259", "other_id": null, "pages": "1977-83", "pmc": null, "pmid": "17161351", "pubdate": "2006-12-20", "publication_types": "D016428:Journal Article", "references": null, "title": "Immunosuppression based on mycophenolate mofetil in stable liver transplanted patients.", "title_normalized": "immunosuppression based on mycophenolate mofetil in stable liver transplanted patients" }

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IMMUNOSUPPRESSION BASED ON MYCOPHENOLATE MOFETIL IN STABLE LIVER TRANSPLANTED PATIENTS. INTERNATIONAL IMMUNOPHARMACOLOGY. 2006?6:1977-83", "literaturereference_normalized": "immunosuppression based on mycophenolate mofetil in stable liver transplanted patients", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20200423", "receivedate": "20200423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17702454, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "NVSC2020ES107718", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILBAO I, CASTELLS L, ROJAS L, CANCINO J, DOPAZO C, CASTRO E ET AL.. IMMUNOSUPPRESSION BASED ON MYCOPHENOLATE MOFETIL IN STABLE LIVER TRANSPLANTED PATIENTS. 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IMMUNOSUPPRESSION BASED ON MYCOPHENOLATE MOFETIL IN STABLE LIVER TRANSPLANTED PATIENTS. INTERNATIONAL IMMUNOPHARMACOLOGY. 2006?6:1977-83", "literaturereference_normalized": "immunosuppression based on mycophenolate mofetil in stable liver transplanted patients", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20200422", "receivedate": "20200422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17694082, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "OBJECTIVE\nOptimal treatment strategies for advanced natural killer/T (NK/T)-cell lymphoma have not been fully defined. We compared the safety and efficacy of DDGP and SMILE regimens for advanced NK/T-cell lymphoma in a randomized controlled, multicenter, and open-label clinical trial.\n\n\nMETHODS\nPatients were newly diagnosed in stages III-IV and had performance scores in 0 to 2. Six cycles of DDGP (dexamethasone, cisplatin, gemcitabline, and pegaspargase) or SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy were randomly assigned to them. The primary end point was progression-free survival (PFS). Secondary end points included response rate and overall survival (OS). The trial is ongoing and is registered with ClinicalTrials.gov (No. NCT01501149).\n\n\nRESULTS\nOf 42 patients enrolled, 21 were treated with DDGP therapy, and 21 patients were treated with SMILE therapy. The 1-year PFS and 2-year OS rates were better in the DDGP group than that in the SMILE group (86% vs. 38% for 1-year PFS, P = 0.006; 74% vs. 45% for 2-year OS, P = 0.027). Complete remission (CR) rate and overall response rate (ORR) of the DDGP group were higher than that in the SMILE group (71% vs. 29%, P = 0.005 for CR rate; 95% vs. 67%, P = 0.018 for ORR). The SMILE group showed more serious leucopenia (P = 0.030) and severe allergic reaction (P = 0.015) than the DDGP group. In addition, two cases in the SMILE group underwent grade 4 mucosal reaction.\n\n\nCONCLUSIONS\nDDGP chemotherapy resulted in significant improvement in PFS, OS, and better tolerability compared with SMILE chemotherapy for newly diagnosed advanced NK/T-cell lymphoma patients. Clin Cancer Res; 22(21); 5223-8. ©2016 AACR.", "affiliations": "Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China.;Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.;Department of Hematology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.;Department of Oncology, Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu, China.;Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.;Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan, China. [email protected].", "authors": "Li|Xin|X|;Cui|Yingying|Y|;Sun|Zhenchang|Z|;Zhang|Lei|L|;Li|Ling|L|;Wang|Xinhua|X|;Wu|Jingjing|J|;Fu|Xiaorui|X|;Ma|Wang|W|;Zhang|Xudong|X|;Chang|Yu|Y|;Nan|Feifei|F|;Li|Wencai|W|;Su|Liping|L|;Wang|Jinghua|J|;Xue|Hongwei|H|;Zhang|Mingzhi|M|", "chemical_list": "D003841:Deoxycytidine; D011092:Polyethylene Glycols; D005047:Etoposide; C042705:pegaspargase; D003907:Dexamethasone; C056507:gemcitabine; D001215:Asparaginase; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1158/1078-0432.CCR-16-0153", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0432", "issue": "22(21)", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "keywords": null, "medline_ta": "Clin Cancer Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002681:China; D002945:Cisplatin; D003841:Deoxycytidine; D003907:Dexamethasone; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D055611:Natural Killer T-Cells; D009364:Neoplasm Recurrence, Local; D011092:Polyethylene Glycols; D012074:Remission Induction; D055815:Young Adult", "nlm_unique_id": "9502500", "other_id": null, "pages": "5223-5228", "pmc": null, "pmid": "27060152", "pubdate": "2016-11-01", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": null, "title": "DDGP versus SMILE in Newly Diagnosed Advanced Natural Killer/T-Cell Lymphoma: A Randomized Controlled, Multicenter, Open-label Study in China.", "title_normalized": "ddgp versus smile in newly diagnosed advanced natural killer t cell lymphoma a randomized controlled multicenter open label study in china" }

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{ "abstract": "BACKGROUND\nChildhood cancer survivors treated with anthracycline chemotherapy are at an increased risk of long-term cardiac toxicity, and guidelines recommend that exposed survivors undergo echocardiography every 1-5 years. However, it is unclear whether survivors should undergo echocardiographic screening indefinitely, or if a period of echocardiographic stability indicates that screening is no longer necessary. The objective of this study was to evaluate the outcomes of echocardiographic screening to aid in the refinement of existing guidelines.\n\n\nMETHODS\nWe retrospectively analyzed the results of echocardiographic screening in a cohort of adult survivors of childhood cancer treated with anthracyclines and/or cardiac radiation therapy. Interval regression analysis was performed to identify predictors of single-episode or sustained abnormal echocardiograms.\n\n\nRESULTS\nThe cohort constituted 333 survivors, with median follow-up time of 15.8 years post-treatment (range: 5.0-47.9), and median age at treatment of 8 years (range: 1.5-18). Forty-nine survivors had an abnormal echocardiogram (14.7%), and 29 (8.7%) had reproducible abnormal findings. An ongoing continual increase in the incidence of sustained echocardiographic abnormality was seen among patients treated with >250 mg/m(2) doxorubicin at age <5 years, reaching 43% by 20 years of therapy. In contrast, no sustained abnormal echocardiographic findings arose after 10 years of therapy in survivors treated with <250 mg/m(2) at age ≥5 years.\n\n\nCONCLUSIONS\nSingle-episode echocardiographic abnormalities are often not reproduced in subsequent evaluations. The duration of echocardiographic screening for childhood cancer survivors should be reassessed for patients who received lower doses of anthracycline after age 5.", "affiliations": "Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Princess Noorah Oncology Center, King Abdulaziz Medical City, Saudi Arabia.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Adult Cardiology, Toronto Western Hospital, Toronto, Ontario, Canada.;Division of Hematology/Oncology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.", "authors": "Ramjaun|Aliya|A|;AlDuhaiby|Eman|E|;Ahmed|Sameera|S|;Wang|Lisa|L|;Yu|Eric|E|;Nathan|Paul C|PC|;Hodgson|David C|DC|", "chemical_list": "D018943:Anthracyclines", "country": "United States", "delete": false, "doi": "10.1002/pbc.25651", "fulltext": "\n==== Front\nPediatr Blood CancerPediatr Blood CancerpbcPediatric Blood & Cancer1545-50091545-5017Blackwell Publishing Ltd Oxford, UK 10.1002/pbc.25651Research ArticlesEchocardiographic Detection of Cardiac Dysfunction in Childhood Cancer Survivors: How Long Is Screening Required? Ramjaun Aliya MSc1AlDuhaiby Eman MD, FRCPC2Ahmed Sameera MSc1Wang Lisa MSc3Yu Eric MD, FRCPC4Nathan Paul C MD, MSc, FRCPC5Hodgson David C MD, MPH, FRCPC156*1 Radiation Medicine Program, Princess Margaret Cancer CentreToronto, Ontario, Canada2 Princess Noorah Oncology CenterKing Abdulaziz Medical City, Saudi Arabia3 Department of Biostatistics, Princess Margaret Cancer CentreToronto, Ontario, Canada4 Division of Adult Cardiology, Toronto Western HospitalToronto, Ontario, Canada5 Division of Hematology/Oncology, The Hospital for Sick Children and University of TorontoToronto, Ontario, Canada6 Department of Radiation Oncology, University of TorontoToronto, Ontario, Canada*Correspondence to: David Hodgson, Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5E 2M9., E-mail: [email protected] of interest: Nothing to declare.\n\n[The copyright line for this article was changed in October 2015 after original online publication.]\n\n12 2015 06 7 2015 62 12 2197 2203 06 10 2014 09 6 2015 © 2015 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals, Inc.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Background\nChildhood cancer survivors treated with anthracycline chemotherapy are at an increased risk of long-term cardiac toxicity, and guidelines recommend that exposed survivors undergo echocardiography every 1–5 years. However, it is unclear whether survivors should undergo echocardiographic screening indefinitely, or if a period of echocardiographic stability indicates that screening is no longer necessary. The objective of this study was to evaluate the outcomes of echocardiographic screening to aid in the refinement of existing guidelines.\n\nMethods\nWe retrospectively analyzed the results of echocardiographic screening in a cohort of adult survivors of childhood cancer treated with anthracyclines and/or cardiac radiation therapy. Interval regression analysis was performed to identify predictors of single-episode or sustained abnormal echocardiograms.\n\nResults\nThe cohort constituted 333 survivors, with median follow-up time of 15.8 years post-treatment (range: 5.0–47.9), and median age at treatment of 8 years (range: 1.5–18). Forty-nine survivors had an abnormal echocardiogram (14.7%), and 29 (8.7%) had reproducible abnormal findings. An ongoing continual increase in the incidence of sustained echocardiographic abnormality was seen among patients treated with >250 mg/m2 doxorubicin at age <5 years, reaching 43% by 20 years of therapy. In contrast, no sustained abnormal echocardiographic findings arose after 10 years of therapy in survivors treated with <250 mg/m2 at age ≥5 years.\n\nConclusions\nSingle-episode echocardiographic abnormalities are often not reproduced in subsequent evaluations. The duration of echocardiographic screening for childhood cancer survivors should be reassessed for patients who received lower doses of anthracycline after age 5. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.\n\nanthracyclinecardiotoxicitypediatric cancersurvivorship\n==== Body\nINTRODUCTION\nAs survival rates for childhood cancer improve, reducing the long-term toxicities of treatment has emerged as a priority in pediatric oncology. Among the most significant complications of pediatric cancer treatment is the occurrence of cardiac morbidity, occurring in up to 57% of survivors treated with anthracycline chemotherapy.[1] The receipt of radiation therapy (RT) to the heart is also strongly associated with cardiac morbidity in these patients.[2]\n\nRecognizing these risks, expert groups have published consensus-based follow-up guidelines intended to detect early clinical indicators of cardiac dysfunction, with the aim of reducing long-term cardiac morbidity. However, significant limitations in existing echocardiographic screening data have resulted in discordance in surveillance recommendations.[3] The Children's Oncology Group (COG), for example, recommends lifelong echocardiographic screening beginning 2 years post-treatment for survivors treated with anthracyclines and/or mediastinal RT, at a frequency of every 1–5 years, depending on treatment age, anthracycline dose, and RT exposure.[4] In contrast, Scottish Intercollegiate Guidelines recommend screening every 2–3 years for patients at greater risk of anthracycline-induced cardiotoxicity, without recommending a screening duration.[5]\n\nChallenges applying the findings of the existing literature to clinical practice arise for several reasons. Many studies have compared the average ventricular function measures from anthracycline-exposed patients to the average results among non-exposed survivors.[6–10] This approach does not reveal the proportion of anthracycline-exposed survivors who will develop abnormal ventricular function indices over time, for whom screening may be beneficial. Follow-up duration is limited in some studies, so that it is not known whether it is necessary to continue screening indefinitely in all patients, or whether a series of normal echocardiograms indicates that future tests are unlikely to be clinically useful. Consequently, guidelines are inconsistent on the optimal duration of screening. Finally, although high rates of echocardiographic abnormalities have been reported among survivors,[11] many studies report on one-time echocardiographic abnormalities. However, the reproducibility and clinical significance of single-episode abnormalities are uncertain, and the benefit of early detection is inferred largely from elderly patients with complex cardiac pathology.[12–14] Consequently, although routine echocardiographic screening has the appeal of potentially detecting pre-symptomatic heart disease at a time when intervention may prevent further deterioration, it is also possible that for some patients, it is unnecessary and detects abnormalities of no clinical consequence.[15,16]\n\nThe purpose of this study was to help establish optimal use of echocardiographic screening by identifying risk factors associated with sustained echocardiographic abnormalities among pediatric cancer survivors, and to describe the incidence of clinically significant late-onset cardiac morbidity among survivors with an extended post-treatment follow-up.\n\nMETHODOLOGY\nStudy Design and Setting\nThe study cohort comprised adult survivors of pediatric cancer managed in the Aftercare program at the Princess Margaret Cancer Centre in Toronto, Canada. Eligible patients were diagnosed with a malignancy before age 18, had attained age ≥18 years, were treated with anthracyclines and/or cardiac RT, had ≥5 years of follow-up post-treatment, and at least one echocardiogram after 1 year of completing therapy. Date of treatment completion was ascertained through patient chart review (i.e., date of last radiation treatment or final chemotherapy cycle). As the study focus was not acute congestive heart failure, patients with a history of acute ventricular dysfunction arising within 1 year of completing therapy were excluded. The institutional research ethics board of the Princess Margaret Cancer Centre approved the study.\n\nMedical Record Abstraction\nDemographic information, including age at diagnosis, sex, age at treatment completion and length of follow-up, was collected, along with patient data on history of hypertension, diabetes mellitus, and smoking status. Anthracyclines included doxorubicin, daunomycin, and epirubicin. Anthracycline doses were converted to doxorubicin-equivalent dose using a conversion factor of 0.83 for daunomycin and 0.67 for epirubicin.[17]\n\nEchocardiography\nAll echocardiograms were performed at a tertiary cardiac care center according to the Ontario Cardiac Care Network Quality Standards.[18] Echocardiography was ordered using a risk-based frequency defined in the follow-up guidelines of the Children's Oncology Group.[4] Echocardiographic parameters, obtained from original reports, included ejection fraction (EF) and shortening fraction (SF). An echocardiogram was considered abnormal if EF <55% or SF <28%[19] or if valvular abnormalities were described as more than “trivial.” Patients with significant abnormalities were referred to a cardiologist for further management. Survivors were considered to have “any” abnormality when there was at least one abnormal echocardiogram, regardless of subsequent echocardiographic results. A “sustained” abnormality was defined as an abnormal echocardiogram followed by one or more consecutive abnormal echocardiograms.\n\nStatistical Analysis\nChi-square tests were performed to compare categorical variables and two sample t-tests were used to assess continuous variables. Interval regression analyses were performed to identify predictors of time to any abnormal echocardiogram, and to sustained abnormal echocardiograms. This method fits a parametric model to failure time data that can be right, left, or interval-censored, and accounts for cases in which the initial abnormal echocardiogram was found at the first visit, and also for variation in timing and frequency of echocardiography among patients in different risk groups. The following variables were assessed through bivariate analysis: age, anthracycline dose, number and frequency of echocardiograms performed, RT receipt, smoking status and a history of hypertension described in the medical record. Variables ultimately included in multivariate analyses were selected on the basis of statistical significance, clinical importance, and confounding. The incidence of abnormal echocardiography was estimated using interval censoring and plotted based on a nonparametric maximum likelihood estimator using Turnbull's algorithm.[20] All analyses were performed using SAS (version 9.3: SAS Institute, Cary, NC). Plots were produced using R statistical software.[21]\n\nRESULTS\nFour hundred and twenty-one patients met inclusion criteria. Seventy-nine were excluded as they had no echocardiographic data available, and nine were excluded due to incomplete and/or missing data on treatment-related variables. Excluded patients were more likely to have leukemia than included patients (44% vs. 30%) and less likely to have lymphoma (36% vs. 47%, P = 0.02 for difference in diagnoses), were more likely to be ≥5 years old at diagnosis (85% vs. 67%, P = 0.001), but did not differ significantly with respect to cumulative anthracycline dose (P = 0.27). The remaining 333 survivors were analyzed.\n\nPatient demographic and clinical characteristics are summarized in Table I. Overall, 224 (67.3%) of those included in the study were ≥5 years of age at the time of initial cancer treatment. The majority of patients (69.1%) were treated with a doxorubicin-equivalent dose <250 mg/m2 and 130 (39%) patients received thoracic RT (median prescribed dose = 15 Gy, range 10–45 Gy). The mean doxorubicin-equivalent dose was significantly higher in patients with sustained abnormal echocardiography at 295 mg/m2 (P < 0.001). The median number of echocardiograms performed was 2 (range: 1–13), with 96 patients having one echocardiogram. The median follow-up time post-treatment was 15.8 years (range: 5.0–47.9 years). The median interval between the end of treatment and the first echocardiogram was 5.7 years (range 0.9–48.0 years) and the median interval between echocardiograms was 2.2 years (range 0.1–19.4 years). Following an abnormal echocardiogram, the median interval to the next echocardiogram was 1.5 years.\n\nTABLE I Demographics, Treatment and Follow-Up Characteristics\n\n\t% (N) or mean (SD)\t\nAge, mean (SD)\t8.47 (4.92)\t\n 1–4 years, % (No.)\t32.73 (109)\t\n ≥5 years, % (No.)\t67.27 (224)\t\nMale sex, % (No.)\t49.25 (164)\t\nDiagnosis, % (No.)\t\t\n Hodgkin lymphoma\t35.44 (118)\t\n ALL\t43.54 (145)\t\n Wilm tumor\t10.21 (34)\t\n Ewing sarcoma\t3.90 (13)\t\n Osteosarcoma\t3.30 (11)\t\n Rhabdomyosarcoma\t2.10 (7)\t\n Lymphoma\t0.60 (2)\t\n Undifferentiated sarcoma\t0.60 (2)\t\n Angiosarcoma\t0.30 (1)\t\nDoxorubicin dose (mg/m2), mean (SD)a\t212.9 (103.52)\t\nRadiotherapy receipt, % (No.)b\t39.04 (130)\t\nAge x Anthracycline Dose, % (No.)\t23.12 (77)\t\n 1–4 years + 1–250 mg/m2\t9.61 (32)\t\n 1–4 years + ≥250 mg/m2\t52.55 (175)\t\n ≥5 + 1–250 mg/m2\t14.71 (49)\t\n ≥5 + ≥ 250 mg/m2\t10.51 (35)\t\n Any age + no anthracycline\t\t\nConventional cardiac risk factors\t\t\n Smoking (former)\t3.3 (11)\t\n Smoking (current at last follow-up)\t10.2 (34)\t\n Hypertension (ever)\t3.6 (13)\t\n Diabetes (ever)\t2.1 (7)\t\nNo. echocardiograms, mean (SD)c\t2.86 (2.10)\t\na Anthracycline drugs included doxorubicin, daunomycin, and epirubicin. Anthracycline doses were converted to doxorubicin equivalent dose by using conversion factor 0.83 for daunomycin and 0.67 for epirubicin.\n\nb Radiation received by the heart.\n\nc Number of echocardiograms received.\n\nAny Echocardiographic Abnormality\nForty-nine patients (14.7%) had at least one abnormal echocardiogram during the follow-up period. The median time to first abnormal echocardiogram was 11.7 years post-treatment (range: 1.8–42.0 years). The probability of having any echocardiographic abnormality steadily increased and reached 20% by 20 years (Fig. 1). Thirty-nine (79.5%) and 28 patients (57.1%) had an abnormality in EF and SF, respectively. Three patients (6.1%) had a valvular abnormality.\n\nFig. 1 (A) Probability of producing an abnormal echocardiogram. (B) Probability of producing an abnormal sustained echocardiogram.\n\nThe 10-year probabilities of having an abnormal echocardiogram among patients, <250 mg/m2 and ≥250 mg/m2 were 8.3% (95% CI = 4.2–12.3%) and 23.3% (95% CI = 12.5–32.7%), respectively. By 20 years after treatment, these rates were 19.5% (95% CI = 8.3–29.2%) and 36.9% (95% CI = 22.8–48.4%), respectively (P < 0.001, Fig. 2). No echocardiographic abnormalities were noted in the first 20 years of follow-up among patients treated with thoracic RT without anthracyclines. The results of univariate interval regression analyses indicated that an anthracycline dose ≥250 mg/m2 was associated with a significantly greater risk of having any abnormal echocardiogram (P < 0.01; Table II). In multivariate analysis, this association remained statistically significant (P < 0.01; Table II). Receipt of mediastinal RT was not significantly associated with abnormal findings.\n\nFig. 2 Cumulative incidence of abnormal echocardiography stratified by age at treatment (A,B) and by anthracycline dose (C,D).\n\nTABLE II Univariate and Multivariate Interval Regression Analyses for any Abnormal Echocardiogram\n\n\tUnivariate\tMultivariate\t\n\tCoefficientb (95% CI)\tP-value\tCoefficient (95% CI)a\tP-value\t\nAge category\t\t\t\t\t\n Age ≥5 years\tReference\t—\tReference\t—\t\n Age <5 years\t−0.54 (−1.13, 0.046)\t0.0711\t−0.34 (−0.85, 0.17)\t0.186\t\nAnthracycline dose\t\t\t\t\t\n None\tReference\t−\tReference\t−\t\n 1–250 mg/m2\t−1.10 (−2.32, 0.12)\t0.0783\t0.97 (−2.23, 0.29)\t0.130\t\n ≥250 mg/m2\t−2.06 (−3.34, −0.77)\t<0.01\t−1.95 (−3.26, −0.64)\t<0.01\t\nNo. of echocardiogramsb\t0.15 (−0.059, 0.35)\t0.163\t—\t—\t\nEchocardiogram frequency\t0.041 (0.0085, 0.074)\t0.014\t—c\t—\t\nRT receipt\t\t\t\t\t\n No RT\tReference\t—\tReference\t—\t\n RT received\t0.50 (−0.065, 1.06)\t0.083\t0.27 (−0.26, 0.81)\t0.312\t\nSmoking status\t\t\t\t\t\n Never smoked\tReference\t—\t—\t—\t\n Ever smoked\t−0.20 (−0.93, 0.53)\t0.590\t—\t—\t\nHypertension\t\t\t\t\t\n Non-hypertensive\tReference\t—\t—\t—\t\n Hypertensive\t−0.27 (−1.29, 0.75)\t0.6002\t—\t—\t\nDiabetes\t\t\t\t\t\n Non-diabetic\tReference\t—\t—\t—\t\n Diabetic\t0.40 (−1.47, 2.27)\t0.6733\t—\t—\t\na A negative coefficient indicates an increased likelihood of having an abnormal echocardiogram (i.e., reduced time to abnormal echocardiography).\n\nb Number of normal echocardiograms prior to first abnormal echocardiogram.\n\nc Echocardiogram frequency was not significant after adjusting for age and treatment and was therefore omitted from the final model.\n\nThe 10-year probabilities of abnormal echocardiography among patients ages 1–4 years and ≥5 years at the time of treatment were 13.6% (95% CI = 6.6–20.1%) and 10.9% (95% CI = 5.9–15.5%), respectively. By 20 years after treatment, these rates had increased to 26.7% (95% CI = 15.7–36.2%) and 14.5% (95% CI = 7.9–20.7%), respectively (Fig. 2). Although the incidence of abnormal echocardiograms in the younger group increased steadily during this 20-year period, few abnormal echocardiograms were observed beyond 15 years in those receiving chemotherapy at ≥5 years of age. Age <5 years at treatment had a borderline association with developing an abnormal echocardiogram (P = 0.07), but this was not significant in multivariate analysis (Table II). When stratified by age and anthracycline dose, the 20-year rates abnormal echocardiography were 11% (≥5 years + <250 mg/m2), 18% (<5 + <250 mg/m2), 29% (≥5 years + ≥250 mg/m2), and 49% (<5 years + ≥250 mg/m2, P = 0.01).\n\nSustained Echocardiographic Abnormality\nTwenty-nine patients (8.7%) had sustained abnormal echocardiography. For nine patients (2.7%), the results of only one echocardiogram were retrievable, and therefore, we were unable to determine whether abnormal echocardiography was sustained or not. This means there were, at minimum, 11 patients with non-sustained abnormal echocardiography, none of which received any cardiac pharmacologic treatment that could account for subsequent normal echocardiography. The 20-year probability of having a sustained echocardiographic abnormality was 15.7% (95% CI = 11–21%; Fig. 1). Younger treatment age and anthracycline dose ≥250 mg/m2 were significantly associated with the development of sustained echocardiographic abnormalities in both univariate and multivariate analyses (P = 0.032; Table III). The 20-year probabilities of having sustained abnormal echocardiography among patients receiving 0 mg/m2, <250 mg/m2, and ≥250 mg/m2 were 0%, 10.2%, and 35.5%, respectively. Over the entire follow-up duration, there was a consistent increase in the incidence of sustained echocardiographic abnormalities among individuals that received ≥250 mg/m2, whereas the probability of having a sustained abnormal echocardiogram may have plateaued by year 15 in the <250 mg/m2 group (Fig. 2).\n\nTABLE III Univariate and Multivariate Interval Regression Analyses for Sustained Abnormal Echocardiograms Only\n\n\tUnivariate\tMultivariate\t\n\tCoefficientb (95% CI)\tP-value\tCoefficient (95% CI)a\tp-value\t\nAge category\t\t\t\t\t\n Age ≥5 years\tReference\t—\tReference\t—\t\n Age <5 years\t−0.89 (−1.64, 0.15)\t0.019\t−0.72 (−1.37, −0.06)\t0.033\t\nAnthracycline dose\t\t\t\t\t\n None\tReference\t—\t—\t—\t\n <250 mg/m2\t−0.99 (−2.47, 0.50)\t0.194\t−0.96 (−2.53, 0.61)\t0.229\t\n ≥250 mg/m2\t−2.10 (−3.65, −0.56)\t<0.01\t−2.10 (−3.72, −0.48)\t0.011\t\nNo. of echocardiogramsb\t−0.042 (−0.22, 0.13)\t0.64\t—\t—\t\nEchocardiogram frequency\t0.062 (0.019, 0.11)\t<0.01\t—c\t—\t\nRT receipt\t\t\t\t\t\n No RT\tReference\t—\tReference\t—\t\n RT received\t0.19 (−0.41, 0.79)\t0.53\t−0.028 (−0.60, 0.55)\t0.925\t\nSmoking status\t\t\t\t\t\n Never smoked\tReference\t—\t—\t—\t\n Ever smoked\t−0.59 (−1.32, 0.14)\t0.114\t—\t—\t\nHypertension\t\t\t\t\t\n Non-hypertensive\tReference\t—\t—\t—\t\n Hypertensive\t−0.70 (−1.70, 0.30)\t0.172\t—\t—\t\nDiabetesd\t\t\t\t\t\n Non-diabetic\tReference\t—\t—\t—\t\n Diabetic\t—\t—\t—\t—\t\na A negative coefficient indicates an increased likelihood of having an abnormal echocardiogram or reduced time to abnormal echocardiography.\n\nb Number of normal echocardiograms prior to first abnormal echocardiogram.\n\nc Echocardiogram frequency was not significant in multivariable analysis with age and treatment exposures, and therefore was excluded from the final model.\n\nd A univariate analysis was not performed with the diabetes variable as no sustained echocardiogram abnormalities were present in individuals with a positive diabetes status.\n\nThe 20-year probabilities of having sustained abnormal echocardiograms among patients aged 1–4 and patients ≥5 years at treatment were 26.2% and 6.9%, respectively. Few events were observed in the older age group beyond 15 years (Fig. 2).\n\nWhen stratified by age and dose, there was a significant (P = 0.01) difference in the risk of having sustained abnormal echocardiography, which was greatest in younger patients that received a high anthracycline dose (20-year risk = 54%, 95% CI = 27–70%; Fig. 3). In contrast, few events occurred among the 162 patients treated with <250 mg/m2 at age ≥5, where the probability of having an abnormal echocardiogram may have plateaued at 5% (95% CI = 1–9%) after 10 years, with no additional sustained abnormalities occurring among the 109 echocardiograms done beyond 10 years post-treatment in this group.\n\nFig. 3 Cumulative incidence of abnormal echocardiography stratified by age at treatment (A) and by anthracycline dose (B).\n\nAdditional Investigations and Medical Interventions\nThirty-five patients (10.4% of all patients) with abnormal echocardiography were referred to a cardiologist. Twenty-four patients underwent additional investigations (e.g., stress echocardiography ± Holter monitoring) following abnormal echocardiography. Sixteen patients (32.6% of those with abnormal echocardiography, 4.8% of the entire cohort) received a medical intervention. Specifically, 13 patients were prescribed angiotensin converting enzyme inhibitors, 10 were prescribed beta blockers, and two were given diuretic medications. Calcium-channel blockers, statins, and digoxin were also prescribed. Nine (69.2%) of these patients were <5 years of age at the time of treatment. Two patients were admitted to hospital for cardiac-related complications. The median time to the initiation of any cardiac treatment was 12.5 years (range: 3.5–47.2 years) post-treatment. No patients died during the course of follow-up.\n\nDISCUSSION\nNon-invasive and widely available echocardiography remains the recommended screening instrument for cardiac abnormalities in childhood cancer survivors.[4] These recommendations are largely based on studies that report a decrement in the average echocardiographic indices of ventricular function among anthracycline-exposed survivors compared to non-exposed survivors.[6,7,22] Although this method of reporting is useful to elucidate factors associated with overall decline in average cardiac performance, it does not provide insight into the proportion of patients likely to benefit from periodic echocardiographic screening. Moreover, there are no data to establish appropriate cardiac screening duration, and existing guidelines make different recommendations on this issue. Our clinical impression is that for many anthracycline-treated patients, indefinite screening is of limited value, but there have been no clinical studies to elucidate the appropriate time to discontinue screening.\n\nOur finding that young age at exposure and higher anthracycline doses (≥250 mg/m.2) were predictive of the risk of abnormal echocardiography is consistent with prior work,[2,23,24] as well as the risk stratification seen across various guidelines. These findings support the use of continued screening among long-term survivors, particularly those exposed to ≥250 mg/m2 prior to age 5, as the incidence of echocardiographic abnormalities continues to rise for at least 25 years post-treatment, with over half of survivors developing sustained evidence of ventricular dysfunction. In contrast, none of the patients treated with <250 mg/m2 after age 5 developed sustained evidence of ventricular dysfunction beyond 10 years of screening. In our cohort, this subgroup accounted for 51.6% of the study population. If these patients could be discharged from routine echocardiographic screening, it would produce a significant reduction in their burden of follow-up, in addition to saving the costs of unnecessary testing.\n\nThe findings of this clinical study are consistent with the results of recent economic simulation studies.[25,26] Wong et al. modeled the cost-effectiveness of different echocardiograph screening schedules for a variety of anthracycline-exposed patient risk-profiles, and estimated that echocardiographic screening at 2-year intervals among patients ≥5 years at diagnosis treated with an anthracycline dose <300 mg/m2, without RT, could be expected to increase per-person life expectancy by less than 3 months, at a cost of $235,000/QALY.[25] Yeh et al. reported similar findings, where the most cost-effective screening strategy in this relatively low-risk group was no assessment.[26] Taken together, it appears that there is an emerging body of evidence that beyond 10 years after exposure, echocardiography is not clinically useful or cost-effective in patients treated with less than 250 mg/m2 after age 5.\n\nStudies in other clinical settings have also shown that as a diagnostic test, echocardiographic results can be user-dependent, and therefore not always reproducible.[27] Our findings further illustrate this limitation of echocardiography as a screening modality, where only 72% of patients with abnormal echocardiography had reproducible results. This illustrates a limitation of some studies that have reported high rates of single-episode echocardiographic abnormalities among survivors,[2,6,27,28] as a significant proportion of exposed patients with an abnormal echocardiogram at a single visit may be misclassified as cases, potentially causing an overestimation of ventricular dysfunction.\n\nThe clinical significance of asymptomatic echocardiographic abnormalities detected in survivors is often uncertain. Much of the assumed benefit of early detection and treatment are inferred from studies of elderly patients with complex cardiac pathology and additional comorbidities.[29–31] It seems possible, however, that many of the echocardiographic abnormalities detected in survivors are of no clear short-term clinical consequence, as with a median follow-up of 15.8 years, only 4.8% of the cohort ultimately required a pharmaceutical intervention. Similarly, a comparison of studies that report the rate of asymptomatic echocardiographic abnormalities to others reporting clinically apparent heart disease reveals the latter to be considerably less common.[32–38] This suggests that improving the value of screening will require increasing the positive-predictive value of the tests employed, and not simply identifying increasingly subtle abnormalities. Large collaborative case-control studies will likely be required evaluating alternative diagnostic tools, possibly in conjunction with assessment of cardiac biomarkers to develop screening protocols that are capable of identifying precursors of significant heart disease.[39,40]\n\nThis study has several limitations that should be considered. First, although the intent was to evaluate echocardiography based on the COG guidelines, irregular attendance among some patients meant that many underwent echocardiograms at inconsistent time intervals. This likely resulted in some delay in detecting cases that would have been considered “events” earlier had an echocardiogram been performed at a scheduled time. We addressed this issue statistically by performing a series of interval regression analyses to account for inconsistent screening schedules. Secondly, we did not distinguish different types of abnormalities in our analyses separately, and some features of ventricular remodeling (e.g., left ventricular posterior wall dimension) were not always specifically reported. Patients with normal ejection fraction may have other more subtle myocardial changes of uncertain clinical significance, and our study did not routinely capture these.[41] Finally, although patients with persistent or clinically significant echocardiographic abnormalities were referred to tertiary care cardiologists with survivorship experience, there was no formalized protocol for treatment. This reflects the lack of data regarding the optimal management for asymptomatic echocardiographic abnormalities for these survivors. Recognizing these issues, we believe our results reflect the likely outcomes of screening in a specialized follow-up care setting, given the inevitable variation in patient attendance and current uncertainty regarding the best echocardiographic parameter to identify clinically important ventricular dysfunction among survivors. We also did not identify RT as a risk factor for developing echocardiographic abnormalities, likely due to the fact that the median RT dose to our patients was low, and RT-associated valvular abnormalities typically occur >20 years after exposure, which is later than the follow-up of most of the patients on this study. Our results would likely not apply to patients with cardiac doses >15 Gy. Further follow-up among patients with higher RT doses would likely reveal the emergence of valvular abnormalities in some patients.\n\nCONCLUSIONS\nChildhood cancer survivors exposed to ≥250 mg/m2 of anthracyclines prior to age 5 had an ongoing risk of developing sustained echocardiographic abnormalities for up to 25 years following treatment. In contrast, patients receiving <250 mg/m2 after age 5 had no new sustained abnormalities detected after 10 years of follow-up, suggesting that prolonged screening for anthracycline-induced cardiomyopathy could be reconsidered in this group. Efforts should be made to improve not only screening sensitivity, but also the specificity of screening to identify clinically important findings.\n\nThis work was funded by the Canadian Cancer Society through the Pediatric Oncology Group of Ontario. The authors extend their thanks to senior graphic artist, Bruna Ariganello.\n==== Refs\nREFERENCES\n1 Lipshultz SE Cochran TR Franco VI Miller TL Treatment-related cardiotoxicity in survivors of childhood cancer Nat Rev Clin Oncol 2013 12 697 710 24165948 \n2 Abosoudah I Greenberg ML Ness KK Benson L Nathan PC Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors Pediatr Blood Cancer 2011 57 467 472 21280201 \n3 Kremer LCM Mulder RL Oeffinger KC Bhatia S Landier W Levitt G Constine LS Wallace HW Caron HN Armenian SH Skinner R Hudson MM A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: A report from the international late effects of Childhood Cancer Guideline Harmonization Group Pediatr Blood Cancer 2013 60 543 549 23281199 \n4 Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. 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A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 1995 333 1670 1676 7477219 \n14 Investigators S Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions N Engl J Med 1992 327 685 691 1463530 \n15 Croswell JM Ransohoff DF Kramer BS Principles of cancer screening: Lessons from history and study design issues Semin Oncol 2010 37 202 215 20709205 \n16 Grimes DA Schulz KF Uses and abuses of screening tests Lancet 2002 359 881 884 11897304 \n17 Shankar SM Marina N Hudson MM Adams JM Landier W Bhatia S Meeske K Chen MH Kinahan KE Monitoring for cardiovascular disease in survivors of childhood cancer: Report from the Cardiovascular Disease Task Force of the Children's Oncology Group Pediatrics 2008 121 e387 e396 18187811 \n18 Standards for provision of echocardiography in Ontario. Toronto, ON, Canada: Cardiac Care Network, 2012 \n19 Lang RM Bierig M Devereux RB Flachskampf FA Foster E Pellikka PA Picard MH Roman MJ Seward J Shanewise JS Solomon SD Spencer KT St John Sutton M Stewart WJ Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology J Am Soc Echocardiogr 2005 18 1440 1463 16376782 \n20 Turnbull BW Nonparametric estimation of a survivorship function with doubly censored data J Am Stat Assoc 1974 69 169 173 \n21 R Development Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2013 \n22 Rathe M Carlsen NLT Oxhøj H Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia Pediatr Blood Cancer 2007 48 663 667 17405151 \n23 Andolina JR Dilley K Anthracycline-induced cardiac toxicity more likely in underweight childhood cancer survivors J Pediatr Hematol Oncol 2010 32 411 415 20495481 \n24 Galper SL James BY Mauch PM Strasser JF Silver B LaCasce A Marcus KJ Stevenson MA Chen MH Ng AK Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation Blood 2011 117 412 418 20858859 \n25 Wong FL Bhatia S Landier W Francisco L Leisenring W Hudson MM Armstrong GT Mertens A Stovall M Robison LL Lyman GH Lipshultz SE Armenian SH Cost-effectiveness of the children's oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure Ann Intern Med 2014 160 672 683 24842414 \n26 Yeh JM Nohria A Diller L Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: A model-based estimation of the clinical and economic effects Ann Intern Med 2014 160 661 671 24842413 \n27 Lipshultz SE Landy DC Lopez-Mitnik G Lipsitz SR Hinkle AS Constine LS French CA Rovitelli AM Proukou C Adams JM Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy J Clin Oncol 2012 JCO.2010.2033.7907 \n28 Hequet O Le Q Moullet I Pauli E Salles G Espinouse D Dumontet C Thieblemont C Arnaud P Antal D Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults J Clin Oncol 2004 22 1864 1871 15143078 \n29 Tsang TS Barnes ME Gersh BJ Takemoto Y Rosales AG Bailey KR Seward JB Prediction of risk for first age-related cardiovascular events in an elderly population: The incremental value of echocardiography J Am Coll Cardiol 2003 42 1199 1205 14522480 \n30 Pastore A Geiger S Baur D Hausmann A Tischer J Horster S Stemmler HJ Cardiotoxicity after anthracycline treatment in survivors of adult cancers: Monitoring by USCOM, echocardiography and Serum biomarkers World J Oncol 2013 4 18 25 \n31 Cardinale D Colombo A Lamantia G Colombo N Civelli M De Giacomi G Rubino M Veglia F Fiorentini C Cipolla CM Anthracycline-induced cardiomyopathy clinical relevance and response to pharmacologic therapy J Am Coll Cardiol 2010 55 213 220 20117401 \n32 Vandecruys E Mondelaers V De Wolf D Benoit Y Suys B Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood J Cancer Surviv 2012 6 95 101 21630046 \n33 Mulrooney DA Yeazel MW Kawashima T Mertens AC Mitby P Stovall M Donaldson SS Green DM Sklar CA Robison LL Leisenring WM Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the Childhood Cancer Survivor Study cohort BMJ 2009 339 b4606 19996459 \n34 Termuhlen AM Tersak JM Liu Q Yasui Y Stovall M Weathers R Deutsch M Sklar CA Oeffinger KC Armstrong G Robison LL Green DM Twenty-five year follow-up of childhood Wilms tumor: A report from the Childhood Cancer Survivor Study Pediatr Blood Cancer 2011 57 1210 1216 21384541 \n35 Kremer LC van Dalen EC Offringa M Ottenkamp J Voute PA Anthracycline-induced clinical heart failure in a cohort of 607 children: Long-term follow-up study J Clin Oncol 2001 19 191 196 11134212 \n36 van Dalen EC van der Pal HJ Kok WE Caron HN Kremer LC Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study Eur J Cancer 2006 42 3191 3198 16987655 \n37 Green DM Grigoriev YA Nan B Takashima JR Norkool PA D'Angio GJ Breslow NE Congestive heart failure after treatment for Wilms' tumor: A report from the National Wilms' Tumor Study group J Clin Oncol 2001 19 1926 1934 11283124 \n38 Creutzig U Diekamp S Zimmermann M Reinhardt D Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML Pediatr Blood Cancer 2007 48 651 662 17183582 \n39 Armstrong GT Plana JC Zhang N Srivastava D Green DM Ness KK Donovan FD Metzger ML Arevalo A Durand JB Screening adult survivors of childhood cancer for cardiomyopathy: Comparison of echocardiography and cardiac magnetic resonance imaging J Clin Oncol 2012 30 2876 2884 22802310 \n40 Monsuez JJ Detection and prevention of cardiac complications of cancer chemotherapy Arch Cardiovasc Dis 2012 105 593 604 23177488 \n41 Armenian SH Gehlehter SK Vase T Venkatramani R Landier W Wilson KD Herrera C Reichman L Menteer JD Mascarenhas L Freyer DR Venkataraman K Bhatia S Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors Clin Cancer Res 2014 20 6314 6323 24947931\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1545-5009", "issue": "62(12)", "journal": "Pediatric blood & cancer", "keywords": "anthracycline; cardiotoxicity; pediatric cancer; survivorship", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000328:Adult; D018943:Anthracyclines; D002648:Child; D002675:Child, Preschool; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D017741:Survivors", "nlm_unique_id": "101186624", "other_id": null, "pages": "2197-203", "pmc": null, "pmid": "26146944", "pubdate": "2015-12", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "11134212;11283124;11356434;11897304;12673729;14522480;1463530;15143078;15837978;16376782;16987655;17183582;17405151;17704413;18187811;18986416;19996459;20117401;20495481;20660845;20709205;20858859;21280201;21384541;21630046;22393080;22802310;23177488;23281199;23535255;24165948;24317971;24842413;24842414;24947931;29147326;7477219", "title": "Echocardiographic Detection of Cardiac Dysfunction in Childhood Cancer Survivors: How Long Is Screening Required?", "title_normalized": "echocardiographic detection of cardiac dysfunction in childhood cancer survivors how long is screening required" }

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ECHOCARDIOGRAPHIC DETECTION OF CARDIAC DYSFUNCTION IN CHILDHOOD CANCER SURVIVORS: HOW LONG IS SCREENING REQUIRED?. PEDIATR BLOOD CANCER 2015?62:2197-2203.", "literaturereference_normalized": "echocardiographic detection of cardiac dysfunction in childhood cancer survivors how long is screening required", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20151116", "receivedate": "20151116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11742022, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "There is a dearth of prospective trials studying treatment response in Persistent Delusional Disorder (PDD) to guide clinical practice. Available retrospective data indicate good response to second-generation antipsychotics (SGAs). We selected the data of patients prescribed either olanzapine or risperidone from a retrospective chart review of PDD (n=455) at our centre. We compared the two groups olanzapine (n =86) versus risperidone (n =280) on dose, drug adherence, response and adverse effects. The two groups were comparable on socio-demographic and clinical characteristics of PDD. There was no statistically significant difference between the two groups on adherence (>80%) and response to treatment (>52% good response). Olanzapine was effective at lower mean chlorpromazine equivalents than risperidone. Logistic regression analysis identified shorter mean duration of illness, good adherence and absence of substance dependence as predictors of good response to both drugs. Our study indicates that acute PDD responds well to treatment with both risperidone and olanzapine, provided adherence can be ensured. In the absence of specific treatment guidelines and randomized controlled trials for PDD, our analysis reaffirms the efficacy of SGAs.", "affiliations": "Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Consultant Psychiatrist, Epworth Hospital, Camberwell, Victoria - 3124 & Honorary Consultant, Department of Psychiatry, Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne, Australia.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Biostatistics, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India.;Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (INI), Bangalore-560029, Karnataka, India. Electronic address: [email protected].", "authors": "Kulkarni|Karishma|K|;Arasappa|Rashmi|R|;Prasad M|Krishna|K|;Zutshi|Amit|A|;Chand|Prabhat K|PK|;Murthy|Pratima|P|;Philip|Mariamma|M|;Muralidharan|Kesavan|K|", "chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine; D002746:Chlorpromazine", "country": "Ireland", "delete": false, "doi": "10.1016/j.psychres.2017.02.066", "fulltext": null, "fulltext_license": null, "issn_linking": "0165-1781", "issue": "253()", "journal": "Psychiatry research", "keywords": "Chlorpromazine equivalents; Logistic regression; Predictors of response; Second generation antipsychotics; Treatment response", "medline_ta": "Psychiatry Res", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002746:Chlorpromazine; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011446:Prospective Studies; D012189:Retrospective Studies; D018967:Risperidone; D012563:Schizophrenia, Paranoid; D016896:Treatment Outcome", "nlm_unique_id": "7911385", "other_id": null, "pages": "270-273", "pmc": null, "pmid": "28411574", "pubdate": "2017-07", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Risperidone versus olanzapine in the acute treatment of Persistent Delusional Disorder: A retrospective analysis.", "title_normalized": "risperidone versus olanzapine in the acute treatment of persistent delusional disorder a retrospective analysis" }

[ { "companynumb": "IN-JNJFOC-20170503763", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "MEAN DOSE: 4.9 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DELUSIONAL DISORDER, UNSPECIFIED TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "MEAN DOSE: 4.9 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSIVE SYMPTOM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tardive dyskinesia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hospitalisation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle rigidity", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Salivary hypersecretion", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse reaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KULKARNI K, ARASAPPA R, PRASAD MK, ZUTSHI A, CHAND PK, MURTHY P, ET AL. RISPERIDONE VERSUS OLANZAPINE IN THE ACUTE TREATMENT OF PERSISTENT DELUSIONAL DISORDER: A RETROSPECTIVE ANALYSIS. PSYCHIATRY RESEARCH 2017?253:270-273. KULKARNI K, ARASAPPA R, PRASAD MK, ZUTSHI A, CHAND PK, MURALIDHARAN K, ET AL. THE IMPACT OF DEPRESSIVE SYMPTOMS ON THE CLINICAL PRESENTATION OF PERSISTENT DELUSIONAL DISORDER. ASIAN JOURNAL OF PSYCHIATRY 2018?32:123-125.", "literaturereference_normalized": "risperidone versus olanzapine in the acute treatment of persistent delusional disorder a retrospective analysis", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20180109", "receivedate": "20170508", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13524256, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" } ]

{ "abstract": "The sting from Centuroides sculpturatus, commonly known as the bark scorpion, is a serious medical problem and can be potentially fatal to young children. Centuroides sculpturatus envenomation can cause a wide spectrum of symptoms, often including autonomic dysfunction, cranial nerve abnormalities, and somatic motor abnormalities. We discuss a 6-month-old male infant who presented with signs and symptoms consistent with bark scorpion envenomation, later found to be secondary to methamphetamine toxicity. Emergency pediatricians should be aware of the strong similarities between scorpion envenomation and methamphetamine toxicity in pediatric patients residing in or having visited the southwestern region of the United States. Methamphetamine toxicity should be considered in their differential diagnosis.", "affiliations": "From the Department of Pediatrics, University of Arizona, Tucson, AZ.", "authors": "Pariury|Holly E|HE|;Steiniger|Aimee M|AM|;Lowe|Merlin C|MC|", "chemical_list": "D000997:Antivenins; D000697:Central Nervous System Stimulants; D012604:Scorpion Venoms; D008694:Methamphetamine", "country": "United States", "delete": false, "doi": "10.1097/PEC.0000000000001301", "fulltext": null, "fulltext_license": null, "issn_linking": "0749-5161", "issue": "33(11)", "journal": "Pediatric emergency care", "keywords": null, "medline_ta": "Pediatr Emerg Care", "mesh_terms": "D000818:Animals; D000997:Antivenins; D000697:Central Nervous System Stimulants; D003937:Diagnosis, Differential; D006801:Humans; D007223:Infant; D008297:Male; D008694:Methamphetamine; D065008:Scorpion Stings; D012604:Scorpion Venoms; D012605:Scorpions", "nlm_unique_id": "8507560", "other_id": null, "pages": "e124-e125", "pmc": null, "pmid": "29095780", "pubdate": "2017-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Stinging Suspicion Something Was Just Not Right: Methamphetamine Toxicity in Infant Mimics Scorpion Envenomation.", "title_normalized": "a stinging suspicion something was just not right methamphetamine toxicity in infant mimics scorpion envenomation" }

[ { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-05301", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "203846", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Eye movement disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Restlessness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Depressed mood", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyskinesia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Irritability", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PARIURY H,STEINIGER A,LOWE M. A STINGING SUSPICION SOMETHING WAS JUST NOT RIGHT METHAMPHETAMINE TOXICITY IN INFANT MIMICS SCORPION ENVENOMATION. PEDIATRIC EMERGENCY CARE 2017?33(11):124-125.", "literaturereference_normalized": "a stinging suspicion something was just not right methamphetamine toxicity in infant mimics scorpion envenomation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180123", "receivedate": "20180104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14349148, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "US-RECORDATI RARE DISEASES-US-R13005-17-00242", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "005378", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pupillary disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Irritability", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Movement disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PARIURY H,STEINIGER A,LOWE M. A STINGING SUSPICION SOMETHING WAS JUST NOT RIGHT: METHAMPHETAMINE TOXICITY IN INFANT MIMICS SCORPION ENVENOMATION. PEDIATRIC EMERGENCY CARE 2017 NOV;33(11):E124-E125.", "literaturereference_normalized": "a stinging suspicion something was just not right methamphetamine toxicity in infant mimics scorpion envenomation", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171117", "receivedate": "20171117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14198125, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "BACKGROUND\nSerotonin syndrome is a potentially fatal complication that usually occurs in the combination use of several serotonergic agents. We presented a patient with major depressive disorder under the treatment of bupropion, trazodone, and quetiapine. Serotonin syndrome developed soon after she received the first session of electroconvulsive therapy (ECT).\n\n\nMETHODS\nThis study is a case report.\n\n\nRESULTS\nA 70-year-old female with major depressive disorder developed serotonin syndrome after the first session of ECT in combination with bupropion, trazodone, and quetiapine. Serotonin syndrome did not reappear in the subsequent ECT treatment while in the treatment with different therapeutic agents.\n\n\nCONCLUSIONS\nThe superimposing effect of ECT in conjunction with serotonergic agents might contribute to the development of serotonin syndrome.", "affiliations": "*Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital; and †Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.", "authors": "Cheng|Ying-Chih|YC|;Liang|Chun-Mao|CM|;Liu|Hsing-Cheng|HC|", "chemical_list": "D017367:Serotonin Uptake Inhibitors; D016642:Bupropion; D000069348:Quetiapine Fumarate; D014196:Trazodone", "country": "United States", "delete": false, "doi": "10.1097/WNF.0000000000000076", "fulltext": null, "fulltext_license": null, "issn_linking": "0362-5664", "issue": "38(3)", "journal": "Clinical neuropharmacology", "keywords": null, "medline_ta": "Clin Neuropharmacol", "mesh_terms": "D000368:Aged; D016642:Bupropion; D003131:Combined Modality Therapy; D003865:Depressive Disorder, Major; D004359:Drug Therapy, Combination; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D000069348:Quetiapine Fumarate; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D014196:Trazodone; D016896:Treatment Outcome", "nlm_unique_id": "7607910", "other_id": null, "pages": "112-3", "pmc": null, "pmid": "25970280", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Serotonin syndrome after electroconvulsive therapy in a patient on trazodone, bupropion, and quetiapine: a case report.", "title_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report" }

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"activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "071405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y-C, LIANG C-M, LIU H-C. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN-NEUROPHARMACOL 2015? 38(3):112-113.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160309", "receivedate": "20150707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11243384, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160525" }, { "companynumb": "TW-WATSON-2016-08690", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "070857", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE HYDROCHLORIDE (WATSON LABORATORIES)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "005", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", 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MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE (UNKNOWN)" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE (UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "070857", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE HYDROCHLORIDE (WATSON LABORATORIES)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "150 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE (ACTAVIS LABORATORIES FL)" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Potentiating drug interaction", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG YC, LIANG CM, LIU HC. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN NEUROPHARMACOL. 2015;38(3):112-3.", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20160504", "receivedate": "20160504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12332968, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-099814", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y-C, LIANG C-M, LIU H-C. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. CLIN-NEUROPHARMACOL. 2015;38(3):112-113", "literaturereference_normalized": "serotonin syndrome after electroconvulsive therapy in a patient on trazodone bupropion and quetiapine a case report", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20150820", "receivedate": "20150707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11242896, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "PHHY2015TW077701", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75584", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75584", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Body temperature increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somatic delusion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorganised speech", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscle rigidity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHENG Y-C, LIANG C-M, LIU H-C.. SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT.. 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SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. 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SEROTONIN SYNDROME AFTER ELECTROCONVULSIVE THERAPY IN A PATIENT ON TRAZODONE, BUPROPION, AND QUETIAPINE: A CASE REPORT. 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{ "abstract": "Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids.", "affiliations": "Department of Respirology, Graduate School of Medicine, Chiba University, Japan.", "authors": "Kasai|Hajime|H|;Terada|Jiro|J|;Hoshi|Hiromasa|H|;Urushibara|Takashi|T|;Kato|Fumiaki|F|;Nishimura|Rintaro|R|;Tatsumi|Koichiro|K|", "chemical_list": "D005938:Glucocorticoids", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.56.7614", "fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7614Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28202865Case ReportRepeated Diffuse Alveolar Hemorrhage in a Patient with Hemophilia B Kasai Hajime 1Terada Jiro 1Hoshi Hiromasa 2Urushibara Takashi 1Kato Fumiaki 1Nishimura Rintaro 1Tatsumi Koichiro 11 Department of Respirology, Graduate School of Medicine, Chiba University, Japan2 Department of Medicine, School of Medicine, Chiba University, JapanCorrespondence to Dr.　Hajime Kasai, [email protected]\n\n15 2 2017 56 4 425 428 21 4 2016 14 6 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids. \n\ndiffuse alveolar hemorrhagehemophiliacorticosteroid\n==== Body\nIntroduction\nDiffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of various clinical entities such as connective tissue disease and a small vessel vasculitis (pulmonary capillaritis); it may also be caused by coagulation disorders (1). Hemophilia, which is a recessive, X-linked congenital bleeding disorder, has rarely been reported in association with DAH. Bleeding in patients with hemophilia mostly occurs internally into the joints or muscles (2). Refractory bleeding after invasive procedures or trauma is a major reason to suspect hemophilia. Although hemophilia is usually diagnosed in adolescence, mild or moderate hemophilia may sometimes escape detection until adulthood (3,4). We herein present the case of a patient with recurrent DAH who was diagnosed with hemophilia B in adulthood.\n\nCase Report\nThe patient was a 48-year-old man who had previously been hospitalized due to hemoptysis at 42 years of age. At that time, a chest radiograph and chest computed tomography (CT) revealed diffuse ground-glass opacity (GGO) in the bilateral lung fields (Fig. 1, 2), and a bronchoscopic examination revealed the accumulation of large amounts of blood in the trachea and bronchi (Fig. 3). The patient's bronchoalveolar lavage fluid (BALF) was bloody and contained numerous hemosiderin-laden macrophages. A culture test of the BALF revealed no findings. An electrocardiogram and transthoracic echocardiogram revealed no abnormalities. A questionnaire that was completed at that time did not reveal the patient's hemorrhagic episode or a family history of bleeding disease, with the exception of his younger brother who had been diagnosed with hepatitis C. Furthermore, he had not received any drugs that had the potential to cause DAH. Following the above-mentioned examinations, DAH due to some sort of vasculitis was suspected. Thus, treatment with high-dose intravenous methylprednisolone (1,000 mg daily) for 3 days followed by prednisolone (25 mg daily) was initiated. This relieved his symptoms. Chest CT showed the resolution of the GGO. The patient's prednisolone dose was tapered and eventually discontinued at two-and-a-half years after his discharge from our hospital.\n\nFigure 1. A chest radiograph at the time of the first admission showed the presence of diffuse ground-glass opacity in the bilateral lung fields.\n\nFigure 2. Chest computed tomography at the time of the first admission showed diffuse ground-glass opacity in the bilateral lung fields.\n\n\nFigure 3. A bronchoscopic examination at the time of the first admission showed the accumulation of a large amount of blood in the trachea and bronchi.\n\n\nThe patient was readmitted to our hospital with a recurrence of hemoptysis at 46 years of age. The above-described therapy was initiated and led to the improvement of his condition. The prednisolone dose was tapered from 60 mg daily to a maintenance dose of 5 mg daily.\n\nAt 48 years of age, he was readmitted to our hospital with a further recurrence of hemoptysis. At this point, he had steroid-induced diabetes mellitus, which was treated with glimepiride (3 mg daily). At admission, his weight was 75 kg and height 167 cm; his vital signs were as follows: blood pressure, 178/102 mmHg; pulse rate, 109 beats/min, pulse oximetry, 97% in room air; and body temperature, 36.8°C. Chest auscultation revealed fine crackles in the right lung field. No skin rash, subcutaneous bleeding or joint swelling were present. A chest radiograph and CT showed the presence of diffuse GGO in the bilateral lung fields. Mild anemia was observed (hemoglobin, 11.3 g/dL), although hemoglobin levels had been 14.6 g/dL prior to the hemoptysis episode. The activated partial thromboplastin time (APTT) was prolonged to 53.5 seconds (normal range, 25.1-40.7 seconds). Laboratory tests showed that the patient's blood glucose and hemoglobin A1c levels were 299 mg/dL and 8.2%, respectively, due to the steroid-induced diabetes mellitus. Autoantibodies for various collagen diseases were negative (Table). We diagnosed the condition as a recurrence of DAH and again administered high-dose intravenous methylprednisolone for 3 days, followed by prednisolone (60 mg daily). His condition improved, as had been observed during the previous episodes. A further detailed inquiry regarding the patient's medical history revealed that, as an elementary school student, he had been hospitalized and had received blood transfusions twice following abnormally heavy bleeding after tooth extraction; however, a specific congenital bleeding disorder had not been diagnosed at that time. It was also revealed that his younger brother had been diagnosed with hemophilia B during adolescence. Considering the possibility of hemophilia, his blood coagulation factors were examined, revealing that his factor IX activity was 3%. The patient was subsequently diagnosed with moderate hemophilia B. By the time of this diagnosis, the patient's DAH had already resolved with the corticosteroid therapy. We decided to continue treating the patient using prednisolone alone, without coagulation factor IX replacement therapy. No recurrence of DAH or hemorrhagic symptoms have been observed during 3 years since the tapering and discontinuation of prednisolone.\n\nTable. Laboratory Data on Admission.\n\nComplete blood count\t\t\tBlood chemistry\t\t\tImmunology\t\t\t\nWBC\t11,400\t/µL\tAST\t30\tU/L\tCRP\t1.3\tmg/dL\t\nNeutrophil\t72.3\t%\tALT\t61\tU/L\tRheumatoid factor\t<5\tunits\t\nEosinophil\t10.7\t%\tLDH\t318\tU/L\tAnti-RNA antibody\tnegative\t\t\nMonocyte\t5.2\t%\tALP\t196\tU/L\tAnti-SS-A/Ro antibody\tnegative\t\t\nLymphocyte\t11.6\t%\tγ-GTP\t113\tU/L\tAnti-SS-B/Ro antibody\tnegative\t\t\nRBC\t411×104\t/µL\tTP\t7\tg/dL\tAnti-centromere antibody\tnegative\t\t\nHGB\t11.3\tg/dL\tALB\t4.3\tg/dL\tAnti-Jo1 antibody\tnegative\t\t\nHCT\t34.5\t%\tUA\t3.9\tmg/dL\tAnti-smith antibody\tnegative\t\t\nPLT\t26.3×104\t/µL\tUN\t13\tmg/dL\tAnti-topoisomerase I antibody\tnegative\t\t\n\t\t\tCRE\t0.73\tmg/dL\tPR3-ANCA\t<10\tEU\t\nCoagulation system\t\t\tT-BIL\t1.1\tmg/dL\tMPO-ANCA\t<10\tEU\t\nAPTT\t53.5\tsec\tID-BIL\t0.1\tmg/dL\tAnti-GBM antibody\t<10\tEU\t\nPT\t11.4\tsec\tNa\t139\tmmol/L\tDouble standard DNA antibody\t<10\tIU/mL\t\nPT activity\t87\t%\tK\t3.7\tmmol/L\tCardiolipin antibody\t<8\tU/mL\t\nPT-INR\t1.03\t\tCl\t104\tmmol/L\t\t\t\t\n\t\t\tGlucose\t299\tmg/dL\tUrine test\t\t\t\n\t\t\tHbA1c\t8.2\t%\tWhite blood cell count\t<1\tHPF\t\n\t\t\t\t\t\tRed blood cell count\t<1\tHPF\t\n\t\t\t\t\t\tUrinary sugar\t4+(1,000)\t\t\nAPTT: activated partial thromboplastin, PT: prothrombin time, PT-INR: PT international normalized ratio, PR3-ANCA: proteinase 3 antineutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-antineutrophil cytoplasmic antibody, GBM: glomerular basement membrane, HPF: high power field\n\nDiscussion\nThe present case raises two clinical issues. First, hemophilia can be associated with repeated DAH and may act as an exacerbating factor. Second, in cases with serious bleeding events, such as DAH in the present case, hemophilia may be overlooked in adolescent patients.\n\nCongenital coagulation disorders, including hemophilia, are known to be the rare causes of DAH (1). In general clinical settings, DAH is mainly caused by pulmonary capillaritis in association with systemic autoimmune diseases, pulmonary renal syndromes, and drugs (5,6). In such cases, treatment with corticosteroids and immunosuppressive agents is often effective. In the present case, the patient's DAH was likely associated with pulmonary capillaritis as it resolved quickly after the initiation of corticosteroid therapy. However, different subtypes of DAH, such as coagulation disorder, mitral stenosis, and acute respiratory distress syndrome, are known to be refractory to corticosteroids and/or immunosuppressive agents. Thus, a careful evaluation is needed in selecting an appropriate treatment for patients with DAH.\n\nSpontaneous hemoptysis as a rare manifestation of DAH in patients with a congenital coagulation disorder. There have only been nine reported cases of hemoptysis occurring with hemophilia; in six of these cases the patients had a concurrent infection (3,7-12). There have been no reports about the frequency of DAH in patients with hemophilia. Although the exact frequency is not known, it is expected to be extremely low. These results suggest that coagulation defectsgenerally play a secondary role in pulmonary hemorrhage and are not a primary cause (8). The occurrence of hemoptysis in patients with hemophilia and other bleeding disorders may therefore indicate the existence of an associated underlying disease (8).\n\nIn the present case, the underlying disease was considered to be some sort of pulmonary capillaritis, with hemophilia B being conducive to bleeding. Corticosteroids are not effective when DAH is caused by hemophilia alone. Hemophilia treatment (other than corticosteroids) was considered for the patient in the present case. Generally, such treatments are determined by the severity of hemophilia, which is classified according to coagulation factor levels as severe (<1%), moderate (1-5%), or mild (5-40%) (13). In cases of moderate hemophilia B, factor IX products are generally replaced at the time that the symptoms appear. In the present case, we continued to treat the patient with prednisolone alone after the second recurrence of DAH, because his hemoptysis had already disappeared in response to corticosteroid therapy at the time of the diagnosis of hemophilia and because the patient's diabetes mellitus and hypertension were controllable with the adjustment of oral hypoglycemic and antihypertensive medications. However, the patient's DAH recurred despite the provision of corticosteroid therapy, this treatment alone may not have been sufficient to achieve the long-term control of DAH. Thus, if it is not possible to control DAH or if other complications such as diabetes mellitus arise due to the corticosteroid therapy, as occurred in the present case, coagulation factor IX replacement therapy is required.\n\nIn the present case, at the time of the first admission, the patient did not recognize that his bleeding episodes were hemorrhagic, and our questioning at the time did not reveal the blood transfusion episodes during his childhood or his brother's medical history. The presence of a mild extended APTT also left us unaware that the patient's condition was complicated with hemophilia. Furthermore, because he showed quite a good response to corticosteroids, we considered pulmonary capillaritis to have been the cause of DAH. Because further inquiries were not, even at the time of first recurrence of DAH, the diagnosis of hemophilia B was delayed. Matsumoto et al. reported the case of an 18-year-old patient with hemophilia B who had tuberculosis with non-cavitary lung disease. He had not been diagnosed in adolescence and presented with recurring hemoptysis (3). They further reported that hemophilia A often escapes detection, even in patients with factor VIII levels as high as 25%, until a heavy bleeding episode after major trauma or surgery (3). These results underscore the importance of performing a repeated, detailed inquiry regarding congenital bleeding diseases, even if DAH shows good response to corticosteroids.\n\nWe herein presented a case in which a patient was diagnosed with hemophilia B after repeated recurrences of DAH. There may be other cases of hemophilia that remain undiagnosed until adulthood. Attention should be paid to the possibility of hemophilia, even in adult patients with an unexplained recurrence of DAH.\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\nKoichiro Tatsumi: Honoraria, GlaxoSmithKline and Pfizer.\n\nKoichiro Tatsumi Research funding, The Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare, Japan.\n==== Refs\n1. Lara AR , Schwarz MI \nDiffuse alveolar hemorrhage . Chest \n137 : 1164 -1171 , 2010 .20442117 \n2. Srivastava A , Brewer AK , Mauser-Bunschoten EP , et al \nGuidelines for the management of hemophilia . Haemophilia \n19 : e1 -e47 , 2013 .22776238 \n3. Matsumoto H , Suzuki K , Watanabe I , et al \nRecurrent hemoptysis in tuberculosis with non-cavitary lung disease as a symptom of mild hemophilia A in a young adult . Intern Med \n39 : 63 -65 , 2000 .10674852 \n4. Peyvandi F , Garagiola I , Young G \nThe past and future of haemophilia: diagnosis, treatments, and its complications . Lancet \n388 : 187 -197 , 2016 .26897598 \n5. Newsome BR , Morales JE \nDiffuse alveolar hemorrhage . South Med J \n104 : 269 -274 , 2011 .21606695 \n6. Specks U \nDiffuse alveolar hemorrhage syndromes . Curr Opin Rheumatol \n13 : 12 -17 , 2001 .11148710 \n7. Suzuki T , Yamamoto Y , Otaki M , et al \nAcute alveolar haemorrhage in a patient with haemophilia B . Haemophilia \n18 : e29 -e31 , 2012 .22004358 \n8. Girolami A , Vettore S , Scandellari R , Allemand E , Girolami B \nAbout the rarity of haemoptysis in congenital bleeding disorders. A report of five cases . Haemophilia \n15 : 825 -827 , 2009 .19444978 \n9. Connolly JP \nHemoptysis as a presentation of mild hemophilia A in an adult . Chest \n103 : 1281 -1282 , 1993 .8131487 \n10. Takeda R , Mabuchi H \nA massive pulmonary hemorrhage resulting in cavitation occurring in a case of hemophilia A associated with diabetes mellitus . South Med J \n67 : 869 -873 , 1974 .4834749 \n11. O'Dwyer ME , DeLoughery TG \nPulmonary hemorrhage in a hemophiliac simulating a lung neoplasm . Am J Hematol \n64 : 299 -302 , 2000 .10911383 \n12. Chandrakala S , Jijina F , Ghosh K \nDiffuse alveolar haemorrhage with severe haemophilia . Haemophilia \n16 : 962 -964 , 2010 .20491960 \n13. White GC 2nd, Rosendaal F , Aledort LM , et al \nDefinitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis . Thromb Haemost \n85 : 560 , 2001 .11307831\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "56(4)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": null, "medline_ta": "Intern Med", "mesh_terms": "D001999:Bronchoscopy; D005938:Glucocorticoids; D002836:Hemophilia B; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "9204241", "other_id": null, "pages": "425-428", "pmc": null, "pmid": "28202865", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10674852;11307831;21606695;19444978;20491960;8131487;10911383;11148710;20442117;22004358;26897598;4834749;22776238", "title": "Repeated Diffuse Alveolar Hemorrhage in a Patient with Hemophilia B.", "title_normalized": "repeated diffuse alveolar hemorrhage in a patient with hemophilia b" }

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{ "abstract": "Anti-tumor necrosis factor (TNF)-α therapy is established as a new standard for the treatment of various autoimmune inflammatory diseases. We report the first case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF-α therapy. A 56-year-old man with Crohn's disease presented with fever and a diffuse, tender goiter. To control the diarrhea, anti-TNF therapy (infliximab) was administered 4 weeks before the thyroid symptoms emerged. The patient reported a swollen neck with tenderness on the right side and fever 4 days after the second infliximab injection. An elevated serum C-reactive protein (CRP) and serum thyroid hormone level with suppressed serum thyrotropin were observed. The thyroid-stimulating antibody was not elevated. An ultrasonograph of the thyroid revealed an enlarged goiter with posterior echogenicity attenuation and a low echoic region that was tender. The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range. The patient was initially diagnosed with thyrotoxicosis resulting from subacute thyroiditis. Administration of oral prednisolone improved the fever, thyroid pain, and thyroid function, but his thyroid remained swollen. The patient developed diarrhea after prednisolone withdrawal; therefore, adalimumab, another TNF inhibitor, was administered. After three injections, his abdominal symptoms were alleviated, but the thyroid pain and fever recurred. Elevated serum CRP levels in the absence of thyroid dysfunction were observed. The patient's symptoms resolved after prednisolone retreatment, but an elastic, firm goiter persisted. A fine-needle biopsy revealed amyloid deposition in the thyroid.\n\n\nCONCLUSIONS\nMany cases with thyroid dysfunction accompanied by amyloid goiter have been reported.There are cases that develop amyloid goiter with subacute thyroiditis-like symptoms after anti-TNF therapy.When the thyroid remains swollen after improvement of thyrotoxicosis following treatment with prednisolone, it should be assessed to differentiate between an amyloid goiter and common subacute thyroiditis.", "affiliations": "Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.;Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.;Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.;Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 , Japan.", "authors": "Kawashima|Junji|J|;Naoe|Hideaki|H|;Sasaki|Yutaka|Y|;Araki|Eiichi|E|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1530/EDM-14-0117", "fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepedmEDM Case ReportsEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 25969738EDM14011710.1530/EDM-14-0117Unique/Unexpected Symptoms or Presentations of a DiseaseA rare case showing subacute thyroiditis-like symptoms with amyloid goiter after anti-tumor necrosis factor therapy Subacute thyroiditis-like symptoms with amyloid goiterKawashima Junji 1Naoe Hideaki 2Sasaki Yutaka 2Araki Eiichi 11 Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan2 Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, JapanCorrespondence should be addressed to J Kawashima Email: [email protected] 5 2015 2015 2015 1401171 4 2015 8 4 2015 © 2015 The authors2015This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nAnti-tumor necrosis factor (TNF)-α therapy is established as a new standard for the treatment of various autoimmune inflammatory diseases. We report the first case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF-α therapy. A 56-year-old man with Crohn's disease presented with fever and a diffuse, tender goiter. To control the diarrhea, anti-TNF therapy (infliximab) was administered 4 weeks before the thyroid symptoms emerged. The patient reported a swollen neck with tenderness on the right side and fever 4 days after the second infliximab injection. An elevated serum C-reactive protein (CRP) and serum thyroid hormone level with suppressed serum thyrotropin were observed. The thyroid-stimulating antibody was not elevated. An ultrasonograph of the thyroid revealed an enlarged goiter with posterior echogenicity attenuation and a low echoic region that was tender. The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range. The patient was initially diagnosed with thyrotoxicosis resulting from subacute thyroiditis. Administration of oral prednisolone improved the fever, thyroid pain, and thyroid function, but his thyroid remained swollen. The patient developed diarrhea after prednisolone withdrawal; therefore, adalimumab, another TNF inhibitor, was administered. After three injections, his abdominal symptoms were alleviated, but the thyroid pain and fever recurred. Elevated serum CRP levels in the absence of thyroid dysfunction were observed. The patient's symptoms resolved after prednisolone retreatment, but an elastic, firm goiter persisted. A fine-needle biopsy revealed amyloid deposition in the thyroid.\n\nLearning points\n\nMany cases with thyroid dysfunction accompanied by amyloid goiter have been reported.\n\nThere are cases that develop amyloid goiter with subacute thyroiditis-like symptoms after anti-TNF therapy.\n\nWhen the thyroid remains swollen after improvement of thyrotoxicosis following treatment with prednisolone, it should be assessed to differentiate between an amyloid goiter and common subacute thyroiditis.\n==== Body\nBackground\nThyroid dysfunction resulting from therapeutic pharmacological agents is often encountered in clinical practice. Various medicines, such as amiodarone and interferon-α, have been reported to induce thyrotoxicosis (1). Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of numerous inflammatory conditions, and its inhibition has proven efficacious in the treatment of autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Recently, several cases of thyrotoxicosis have been reported in association with anti-TNF therapy using etanercept (2)\n(3)\n(4)\n(5). However, thyrotoxicosis accompanied by an amyloid goiter after anti-TNF therapy has never been reported.\n\nIn the present report, we present the first reported case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF therapy for Crohn's disease.\n\nCase presentation\nA 56-year-old man who had been suffering from diarrhea since the age of 50 was diagnosed with Crohn's disease. He had no previous history of a thyroid disease or the use of other medications known to induce thyroid dysfunction. He had no history of neck pain, irradiation, or recent fever and no family history of thyroid disease. At the age of 56 years, he was treated with the TNF inhibitor infliximab (5 mg/kg) on April 26, 2012, and May 9, 2012, to improve diarrhea. He noticed neck swelling with right neck tenderness and fever 4 days after the second injection of infliximab and thus was referred to our department on May 23, 2012.\n\nPhysical examination revealed that he was undernourished, with a height of 1.67 m and a weight of 52.0 kg. His body temperature was 36.5 °C because had been taking acetaminophen since May 13, 2012. His blood pressure was 154/80 mmHg, and his pulse was 71 bpm. He did not have lid retraction, hyperhidrosis, or tremor of the fingers. An elastic, firm goiter was palpable, primarily in the right lobe of the thyroid, which was tender.\n\nInvestigation\nThe laboratory data revealed hypochromic anemia, hypoalbuminemia, and hypolipidemia (Table 1). His renal function was normal, with the exception of a slightly elevated urinary protein level. His serum C-reactive protein (CRP) was elevated, whereas his white blood cell count was within normal range. His serum free triiodothyronine (fT3) and serum free thyroxine (fT4) were both elevated, and his serum thyroid stimulating hormone (TSH) was low. His serum thyroglobulin (Tg) was elevated, and anti-Tg and anti-thyroid peroxidase antibodies were absent. Thyroid-stimulating antibodies were not elevated. Ultrasonography of his thyroid gland revealed an enlarged goiter (estimated thyroid volume: 46.8 ml), particularly in the right lobe, with irregular hypoechoic region in the right lobe and posterior attenuation of echogenicity (Fig. 1). The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range (Fig. 2). Thus, his condition at that time was diagnosed as thyrotoxicosis resulting from subacute thyroiditis but not from Graves’ disease.\n\nTable 1 Laboratory results (May 23, 2012). Values presented in italics are below the normal lower limit, whereas those in bold are above the normal upper limit. Tg-antibody and TPO-antibody were measured by the electrochemiluminescence (ECLIA) method\n\n\nLaboratory tests\n\t\nPatient's values\n\t\nReference range\n\t\nWBC (/mm3)\t4200\t(3500–8500)\t\n Neut. (%)\t70.0\t(40.7–74.8)\t\n Lymp. (%)\t18.5\t(19.0–49.7)\t\n Mono. (%)\t7.2\t(1.0–9.0)\t\n Eosin. (%)\t4.1\t(0–6.6)\t\nRBC (×106 μl)\t3.38\t(4.31–5.65)\t\nHemoglobin (g/dl)\t9.8\t(14.0–17.7)\t\nHematocrit (%)\t29.8\t(40.4–50.8)\t\nPlatelet (/mm3)\t243\t(145–325)\t\nTotal protein (g/dl)\t7.3\t(6.5–8.3)\t\nAlbumin (g/dl)\t3.8\t(3.9–4.9)\t\nNa (mEq/l)\t144\t(138–146)\t\nK (mEq/l)\t3.9\t(3.5–5.0)\t\nCl (mEq/l)\t110\t(99–109)\t\nCa (mg/dl)\t9.5\t(8.3–10.5)\t\nP (mg/dl)\t3.3\t(2.5–4.8)\t\nBUN (mg/dl)\t20.9\t(8–24)\t\nCreatinine (mg/dl)\t0.95\t(0.56–1.18)\t\nAST (U/l)\t30\t(13–34)\t\nALT (U/l)\t31\t(7–37)\t\nγ-GTP (U/l)\t21\t(9–47)\t\nLDH (U/l)\t167\t(112–213)\t\nALP (U/l)\t239\t(106–350)\t\nCHE (U/l)\t207\t(218–464)\t\nCRP (mg/dl)\t3.95\t(<0.3)\t\nBlood glucose (mg/dl)\t73\t(72–110)\t\nT. cholesterol (mg/dl)\t95\t(128–220)\t\nTriglyceride (mg/dl)\t60\t(30–150)\t\nHDL cholesterol (mg/dl)\t43\t(40–108)\t\nTSH (μIU/ml)\t0.02\t(0.50–5.00)\t\nfT3 (pg/ml)\t4.60\t(2.30–4.00)\t\nfT4 (ng/dl)\t1.94\t(0.90–1.70)\t\nThyroglobulin (ng/ml)\t195.7\t(<32.7)\t\nTSAb (%)\t104\t(<180)\t\nTg-antibody (IU/ml)\t0.7\t(<28)\t\nTPO-antibody (IU/ml)\t0.3\t(<16)\t\nWBC, white blood cell; RBC, red blood cell; BUN, blood urea nitrogen; TSAb, thyroid stimulating antibody; Tg, thyroglobulin; TPO, thyroid peroxidase.\n\nFigure 1 Ultrasonograph of the thyroid showing diffuse enlargement and posterior attenuation of echogenicity (A and B). The right lobe had a low echoic region that was tender (C, white arrow). On color Doppler imaging, the thyroid gland did not show hypervascularity (D).\n\nFigure 2 Technetium-99m scintigraph of the thyroid.\n\nTreatment\nAs the administration of acetaminophen for another 2 weeks did not ameliorate his symptoms and thyroid dysfunction, oral prednisolone (20 mg/day) was initiated on June 6, 2012. Instantly, his fever and thyroid pain were improved. Treatment with prednisolone was stopped on November 8, 2012 (Fig. 3) because his thyroid function had normalized and his symptoms were gone. His goiter was reduced in size after the treatment with prednisolone, but it remained swollen.\n\nFigure 3 Changes in thyroid function and CRP. Prednisolone (PSL) was administrated from June 2012 to November 2012 and from January 2013 to April 2013 for the treatment of subacute thyroiditis-like symptoms. Treatment with PSL for Crohn's disease was started in September 2013. Levothyroxine Na was prescribed for hypothyroidism in July 2013. Mesalazine and azathioprine were taken for the treatment of Crohn's disease.\n\nHe suffered from diarrhea after the withdrawal of prednisolone; therefore, another TNF inhibitor, adalimumab, was administered starting on December 13, 2012. After three injections, his abdominal symptoms were ameliorated, but his thyroid pain and fever returned on January 10, 2013. The laboratory data on January 16 revealed elevated serum CRP (9.88 mg/dl) without thyroid dysfunction (Fig. 3). Serum Tg had increased from 200.7 ng/ml (December 5, 2012) to 753.2 ng/ml (January 16, 2013). Adalimumab was discontinued, and oral prednisolone (10 mg daily) was restarted. His symptoms vanished immediately after retreatment with prednisolone, but the elastic, firm goiter in the right lobe remained. A fine-needle biopsy of the thyroid gland was performed on November 7, 2013, and it revealed amyloid deposition in his thyroid gland (Fig. 4). Amyloid deposition was histologically confirmed in biopsied tissues from his stomach and duodenum.\n\nFigure 4 Cytological examination of the thyroid tissue obtained using fine-needle biopsy. Abnormal extracellular deposits showed positive staining with Congo red.\n\nOutcome and follow-up\nAs his serum TSH level increased, levothyroxine has been prescribed since July 2013, which has yielded a euthyroid state (Fig. 3).\n\nDiscussion\nThyrotoxicosis in our patient is suspected to have resulted from subacute thyroiditis-like destructive thyroiditis but not from hyperthyroidism, because his fever and thyroid pain disappeared immediately after the treatment with prednisolone. Relatively low uptake on technetium-99m scintigraphy also strongly suggests destructive thyroiditis.\n\nA viral etiology has most often been implicated in subacute thyroiditis. Although serological tests for viruses suspected to be associated with subacute thyroiditis were not performed, our patient reported no episode of viral infection during anti-TNF therapy. Human leukocyte antigen typing showed that he was positive for B44 and B51 but not for B35, which confers an apparent genetic predisposition to subacute thyroiditis (6).\n\nEarly recurrence of subacute thyroiditis (within 12 months after the first episode) is rare, occurring in only 10% of patients with subacute thyroiditis (7). Our patient immediately relapsed with thyroid pain and fever after the treatment with a different anti-TNF agent. Furthermore, although goiters resulting from subacute thyroiditis usually disappear after improvement in thyroid function, in the present case, the patient's thyroid remained swollen following treatment with prednisolone. Therefore, our patient was suspected of having a thyroid disorder different from common subacute thyroiditis. He was then diagnosed with thyroid amyloidosis by fine-needle biopsy.\n\nAmyloidosis is classified as primary and secondary. Secondary amyloidosis mostly accompanies chronic inflammatory diseases, such as tuberculosis, rheumatoid arthritis, and inflammatory bowel disease. One previous study reported that 15 (0.9%) of 1709 patients with Crohn's disease were complicated by secondary amyloidosis and only three patients had amyloid deposition in the thyroid (8).\n\nThyroid function in patients with an amyloid goiter is usually normal. However, several cases have been reported involving hyperthyroxinemia with an amyloid goiter that might have resulted from destructive thyroiditis, as was the case with our patient (9)\n(10). Although subacute thyroiditis more frequently affects women than men (7), thyroid amyloidosis with subacute thyroiditis-like symptoms has been reported mainly in men.\n\nIt is difficult to verify that the patient had thyroid amyloidosis before the administration of the first anti-TNF inhibitor, infliximab, because he did not undergo any examinations of the thyroid, including ultrasonography or needle biopsy, before the administration of the inhibitor. Serum thyroglobulin was elevated after the administration of the second anti-TNF inhibitor, adalimumab. This strongly suggests that anti-TNF inhibitors triggered the destructive thyroiditis-like subacute thyroiditis in the patient. How TNF inhibitors could trigger subacute thyroiditis-like symptoms in our patient is unknown. Infliximab and adalimumab are monoclonal antibodies directed against TNF-α, and both have been established as a new standard for the treatment of Crohn's disease. A patient who developed Graves’ disease during treatment with adalimumab has been reported (11), but no case involving destructive thyroiditis during treatment with both inhibitors was found in the literature. Etanercept is a TNF inhibitor that acts as a decoy receptor for TNF-α by competitively inhibiting the binding of TNF-α to its cell surface receptor. Several reports describe patients developing thyrotoxicosis while on etanercept (2)\n(3)\n(4)\n(5). All of these patients were initially suspected of having subacute thyroiditis because they showed thyroid pain without thyroid antibodies, but no thyroid amyloidosis was documented. All of these patients happened to develop subacute thyroiditis at least 6 months after the initiation of etanercept treatment. However, the subacute thyroiditis-like symptoms in our patient occurred immediately after the initiation of infliximab and adalimumab.\n\nTNF-α and TNF-α receptors reside in human thyroid tissue (12). Anti-TNF-α antibody suppresses thyroidal fibrosis in mouse with granulomatous experimental autoimmune thyroiditis (13). Therefore, TNF signaling likely regulates the structure and function of the thyroid. Thus, modulation of the immune system by TNF inhibitors that are similar to interferon may induce thyroid dysfunction.\n\nWe described a case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF therapy. The precise mechanism underlying the onset of this condition remains unclear. Further studies are of interest to elucidate the pathogenesis of subacute thyroiditis.\n\nPatient consent\nWritten informed consent was obtained from the patient for publication of this case report.\n\nAuthor contribution statement\nJ Kawashima was the lead clinician who managed the patient's thyroid disorder; H Naoe was the lead clinician who managed the patient's Crohn's disease; all authors contributed to the drafting of the report.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n==== Refs\nReferences\n1 \n\nSurks \nMI \n & \nSievert \nR \n. 1995 \nDrugs and thyroid function . New England Journal of Medicine \n333 \n1688 –1694 . 10.1056/NEJM199512213332507 \n7477223 \n2 \n\nAllanore \nY \n, \nBremont \nC \n, \nKahan \nA \n & \nMenkes \nCJ \n. 2001 \nTransient hyperthyroidism in a patient with rheumatoid arthritis treated by etanercept . Clinical and Experimental Rheumatology \n19 \n356 –357 .11407100 \n3 \n\nVassilopoulos \nD \n, \nSialevris \nK \n, \nMalahtari \nS \n, \nDeutsch \nM \n, \nManolakopoulos \nS \n & \nArchimandritis \nAJ \n. 2010 \nSubacute thyroiditis presenting as fever of unknown origin in a patient with rheumatoid arthritis under etanercept treatment . Journal of Clinical Rheumatology \n16 \n88 –89 . 10.1097/RHU.0b013e3181d0bd30 \n20216130 \n4 \n\nCanas \nCA \n, \nTobon \nGJ \n, \nArango \nLG \n & \nGuarin \nN \n. 2009 \nDeveloping of granulomatous thyroiditis during etanercept therapy . Clinical Rheumatology \n28 \nS17 –S19 . 10.1007/s10067-008-1046-2 \n19043773 \n5 \n\nYasuji \nI \n. 2013 \nSubacute thyroiditis in a patient with juvenile idiopathic arthritis undergoing etanercept treatment: a case report and review of the literature . Modern Rheumatology \n23 \n397 –400 . 10.3109/s10165-012-0670-5 \n22669598 \n6 \n\nOhsako \nN \n, \nTamai \nH \n, \nSudo \nT \n, \nMukuta \nT \n, \nTanaka \nH \n, \nKuma \nK \n, \nKimura \nA \n & \nSasazuki \nT \n. 1995 \nClinical characteristics of subacute thyroiditis classified according to human leukocyte antigen typing . Journal of Clinical Endocrinology and Metabolism \n80 \n3653 –3656 . 10.1210/jcem.80.12.8530615 \n8530615 \n7 \n\nFatourechi \nV \n, \nAniszewski \nJP \n, \nFatourechi \nGZ \n, \nAtkinson \nEJ \n & \nJacobsen \nSJ \n. 2003 \nClinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study . Journal of Clinical Endocrinology and Metabolism \n88 \n2100 –2105 . 10.1210/jc.2002-021799 \n12727961 \n8 \n\nGreenstein \nAJ \n, \nSachar \nDB \n, \nPanday \nAK \n, \nDikman \nSH \n, \nMeyers \nS \n, \nHeimann \nT \n, \nGumaste \nV \n, \nWerther \nJL \n & \nJanowitz \nHD \n. 1992 \nAmyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients . Medicine \n71 \n261 –270 . 10.1097/00005792-199209000-00001 \n1522802 \n9 \n\nIkenoue \nH \n, \nOkamura \nK \n, \nKuroda \nT \n, \nSato \nK \n, \nYoshinari \nM \n & \nFujishima \nM \n. 1988 \nThyroid amyloidosis with recurrent subacute thyroiditis-like syndrome . Journal of Clinical Endocrinology and Metabolism \n67 \n41 –45 . 10.1210/jcem-67-1-41 \n3379135 \n10 \n\nNagai \nY \n, \nOhta \nM \n, \nYokoyama \nH \n, \nTakamura \nT \n & \nKobayashi \nKI \n. 1998 \nAmyloid goiter presented as a subacute thyroiditis-like symptom in a patient with hypersensitivity vasculitis . Endocrine Journal \n45 \n421 –425 . 10.1507/endocrj.45.421 \n9790279 \n11 \n\nvan Lieshout \nAW \n, \nCreemers \nMC \n, \nRadstake \nTR \n, \nElving \nLD \n & \nvan Riel \nPL \n. 2008 \nGraves' disease in a patient with rheumatoid arthritis during treatment with anti-tumor necrosis factor-α . Journal of Rheumatology \n35 \n938 –939 .18464319 \n12 \n\nZubelewicz \nB \n, \nMuc-Wierzgon \nM \n, \nWierzgon \nJ \n, \nRomanowski \nW \n, \nMazurek \nU \n, \nWilczok \nT \n & \nPodwinska \nE \n. 2002 \nGenetic disregulation of gene coding tumor necrosis factor α receptors (TNF α Rs) in follicular thyroid cancer – preliminary report . Journal of Biological Regulators and Homeostatic Agents \n16 \n98 –104 .12144133 \n13 \n\nChen \nK \n, \nWei \nY \n, \nSharp \nGC \n & \nBraley-Mullen \nH \n. 2007 \nDecreasing TNF-α results in less fibrosis and earlier resolution of granulomatous experimental autoimmune thyroiditis . Journal of Leukocyte Biology \n81 \n306 –314 . 10.1189/jlb.0606402 \n17046971\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-0573", "issue": "2015()", "journal": "Endocrinology, diabetes & metabolism case reports", "keywords": null, "medline_ta": "Endocrinol Diabetes Metab Case Rep", "mesh_terms": null, "nlm_unique_id": "101618943", "other_id": null, "pages": "140117", "pmc": null, "pmid": "25969738", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "19043773;12144133;11407100;17046971;20216130;3379135;7477223;12727961;18464319;9790279;8530615;22669598;1522802", "title": "A rare case showing subacute thyroiditis-like symptoms with amyloid goiter after anti-tumor necrosis factor therapy.", "title_normalized": "a rare case showing subacute thyroiditis like symptoms with amyloid goiter after anti tumor necrosis factor therapy" }

[ { "companynumb": "JP-JNJFOC-20131016692", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": "20120509", "drugenddateformat": "102", "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20120509", "drugstartdateformat": "102", "drugstructuredosagenumb": "252", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOSTRIDIUM BUTYRICUM SPORES STRAIN M-55" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIYA-BM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTASA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": "20120426", "drugenddateformat": "102", "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20120426", "drugstartdateformat": "102", "drugstructuredosagenumb": "252", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "52", "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Goitre", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Thyroiditis subacute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2012" } }, "primarysource": { "literaturereference": "KAWASHIMA J, NAOE H, SASAKI Y, ARAKI E. A RARE CASE SHOWING SUBACUTE THYROIDITIS-LIKE SYMPTOMS WITH AMYLOID GOITER AFTER ANTI-TUMOR NECROSIS FACTOR THERAPY.. ENDOCRINOLOGY, DIABETES AND METABOLISM CASE REPORTS MAY-2015:14-0117. KAWASHIMA J, KUKIDOME D, IGATA M, KONDO T, TSURUZOE K, SHIMODA S, ET AL. A CASE OF SUBACUTE THYROIDITIS THAT DEVELOPED AFTER STARTING ANTI-TNF ALPHA ANTIBODY THERAPY TO TREAT CROHN^S DISEASE. THE JAPANESE JOURNAL OF ENDOCRINOLOGY 2013;89 (2):502.", "literaturereference_normalized": "a rare case showing subacute thyroiditis like symptoms with amyloid goiter after anti tumor necrosis factor therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150528", "receivedate": "20131031", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 9659674, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "Nontraditional combination of existing therapies is often the only option to avoid surgery in refractory inflammatory bowel disease (IBD) patients. We aim to assess the efficacy and safety of concomitant use of 2 biologic therapies or combination of biologic and tofacitinib in a refractory pediatric IBD cohort.\n\n\n\nAs part of an ongoing single-center observational cohort study of therapeutic outcomes in pediatric IBD patients (younger than 18 years), data were collected for patients receiving dual therapy. Primary outcome was 6 months of steroid-free remission. Secondary outcomes included time to steroid-free remission, change in serum biomarkers (C-reactive protein and erythrocyte sedimentation rate) and albumin between baseline and 6 months, and adverse events.\n\n\n\nSixteen children (9 ulcerative colitis/IBD-unspecified, 7 Crohn's disease), with a disease duration of 3 (2.1-5.0) years, initiated dual therapy at an age of 15.9 (13.5-16.8) years after failing ≥2 biologic therapies. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn's disease ) achieved steroid-free remission at 6 months. Erythrocyte sedimentation rate and C-reactive protein decreased (P = 0.021 and P = 0.015, respectively) and albumin increased (P = 0.003) between baseline and 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis.\n\n\n\nOur data suggest that dual therapy may be an option for patients with limited therapeutic options remaining. Safety concerns should always be at the forefront of decision-making, and larger studies are needed to help confirm the preliminary safety data observed.", "affiliations": "Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY.", "authors": "Dolinger|Michael T|MT|;Spencer|Elizabeth A|EA|0000-0002-6787-1164;Lai|Joanne|J|;Dunkin|David|D|;Dubinsky|Marla C|MC|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ibd/izaa277", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0998", "issue": "27(8)", "journal": "Inflammatory bowel diseases", "keywords": "Crohn’s disease; biologics; inflammatory bowel disease; pediatric gastroenterology; ulcerative colitis", "medline_ta": "Inflamm Bowel Dis", "mesh_terms": null, "nlm_unique_id": "9508162", "other_id": null, "pages": "1210-1214", "pmc": null, "pmid": "33125058", "pubdate": "2021-07-27", "publication_types": "D016428:Journal Article", "references": null, "title": "Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease.", "title_normalized": "dual biologic and small molecule therapy for the treatment of refractory pediatric inflammatory bowel disease" }

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{ "abstract": "A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML.", "affiliations": "Department of Neurology, Kobe City Medical Center General Hospital, Japan.;Department of Anatomic Pathology, Tokyo Medical University, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, Japan.;Department of Pathology, Kobe City Medical Center General Hospital, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Japan.;Department of Neurology, Kobe City Medical Center General Hospital, Japan.", "authors": "Ishii|Junko|J|;Shishido-Hara|Yukiko|Y|;Kawamoto|Michi|M|;Fujiwara|Satoru|S|;Imai|Yukihiro|Y|;Nakamichi|Kazuo|K|;Kohara|Nobuo|N|", "chemical_list": "D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D015767:Mefloquine", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.0696-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2970994710.2169/internalmedicine.0696-17Case ReportA Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study Ishii Junko 1Shishido-Hara Yukiko 2Kawamoto Michi 1Fujiwara Satoru 1Imai Yukihiro 3Nakamichi Kazuo 4Kohara Nobuo 1\n1 Department of Neurology, Kobe City Medical Center General Hospital, Japan\n2 Department of Anatomic Pathology, Tokyo Medical University, Japan\n3 Department of Pathology, Kobe City Medical Center General Hospital, Japan\n4 Department of Virology 1, National Institute of Infectious Diseases, JapanCorrespondence to Dr.　Junko Ishii, [email protected]\n\n27 4 2018 15 9 2018 57 18 2727 2734 20 12 2017 7 2 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML. \n\nprogressive multifocal leukoencephalopathy (PML)systemic lupus erythematosus (SLE)punctate pattern, pathological examinationearly diagnosismefloquine\n==== Body\nIntroduction\nProgressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by the reactivation of latent JC virus (JCV) infection. Although the life cycle and molecular pathogenesis of JCV have not been completely elucidated yet, nonpathogenic “archetype” JCV may occasionally transform into the “neurotropic type (PML-type)”, which is thought to cause PML according to the “archetype hypothesis” (1-3).\n\nThis disease was previously known as a complication of AIDS, but at present, PML development due to the use of immunomodulatory drugs, such as natalizumab (NTZ) for multiple sclerosis (MS), is a serious concern (4). PML can be comorbid with autoimmune disorders, such as systemic lupus erythematosus (SLE), when the patient is under immunosuppressant therapy (5). Brain magnetic resonance imaging (MRI) in cases of PML typically shows large subcortical lesions with an increased T2-weighted signal and correlates with rapid progression that usually leads to a poor prognosis (6). Recently, in NTZ-treated MS patients, atypical MRI findings with a punctate pattern have been reported as an early sign of PML (7, 8-10), but whether or not these images are also indicative of early PML lesions in non-MS patients is unclear.\n\nWe herein report a case of pathologically-proven PML in a patient with SLE, who showed a punctate MRI pattern and a good clinical course. The pathology suggested a relatively low viral replication in the infected cells that may be indicative of the early demyelinating stage, supporting a better prognosis.\n\nCase Report\nA 37-year-old woman had been diagnosed with SLE at 12 years of age. SLE recurred several times despite combination therapy with high-dose intravenous methylprednisolone, oral prednisolone (PSL), azathioprine (AZA), and 6-mercaptopurine. At 16 and 17 years of age, plasmapheresis and high-dose intravenous cyclophosphamide therapy (IVCY) were introduced, respectively, to control the disease. At 17 years of age, she experienced insomnia, auditory hallucinations, and convulsive seizures, indicating neuropsychiatric SLE (NPSLE). Thus, an antiepileptic drug was temporarily administered. At 18 years of age, she had severe lupus nephritis with nephrotic syndrome. As the lupus nephritis was refractory, the treatment was changed from PSL+AZA+IVCY to PSL+cyclosporine+IVCY at 20 years of age. At 23 years of age, she underwent hemodialysis for about 8 months, and LDL apheresis was introduced. As she experienced convulsive seizures again, NPSLE was suspected and an antiepileptic drug was temporarily administered. At 27 years of age, immunoadsorption plasmapheresis was performed. From 28 years of age, her SLE symptoms were suppressed with PSL+cyclosporine. At 32 years of age, cyclosporine was switched to mycophenolate mofetil (MMF) for better control of the disease. Since then, SLE and lupus nephritis had been relatively well controlled with PSL 8-10 mg/day+MMF 1,000-1,250 mg/day despite a long history of refractory SLE.\n\nApproximately five months before the initial visit to our department, she began experiencing gait disturbance and cognitive dysfunction, and these symptoms slowly became exacerbated. At the initial visit, brain MRI revealed small, punctate, T2-/fluid-attenuated inversion recovery (FLAIR)-hyperintense and T1-hypointense lesions without gadolinium (Gd) enhancement in the bilateral cerebral peduncles, internal capsule, corpus callosum, and deep white matter of the left frontal lobe and bilateral periventricular area (Fig. 1). SLE-related vasculitis was suspected, as she had a long history of refractory SLE and lupus nephritis with NPSLE, and the size and distribution of MRI lesions resembled those reported in patients with NPSLE (11, 12). However, blood tests showed no exacerbation of SLE, and Gd enhancement was not apparent on brain MRI. We also considered PML as a differential diagnosis; however, PML was thought to be unlikely due to the lack of U-fiber involvement and the atypical MR images.\n\nFigure 1. Brain MRI findings at the initial visit (A: FLAIR images, B: T1-weighted images, C: diffusion-weighted images, D: T1-weighted images with gadolinium enhancement). FLAIR images (A) show high-intensity areas in the bilateral cerebral peduncles, internal capsule, corpus callosum, and deep white matter of the left frontal lobe and bilateral periventricular area. These lesions show a small punctate pattern without U-fiber involvement (A: enlarged view). These punctate lesions are scattered in the vicinity of the larger merged lesion in the left frontal lobe. Small punctate lesions are clearly visualized as low-intensity signals on T1-weighted images (B: axial and sagittal) in the deep white matter and internal capsule. The lesions appear as slightly high-intensity signals on diffusion-weighted images (C) and do not show any enhancement after gadolinium administration on T1-weighted images (D). The arrows in the FLAIR image, T1-weighted image, and diffusion-weighted images show the biopsied area (A, B, and C). FLAIR: fluid-attenuated inversion recovery, DWI: diffusion-weighted images, Gd: gadolinium\n\nPolymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) revealed the presence of JCV DNA (at most 500 copies/mL), but repeated trials were sometimes JCV-negative. The serum was positive for anti-JCV antibody (Index 2.24), which is associated with an increased risk of PML in patients with a history of NTZ treatment (4, 13), although this patient had not been treated with NTZ. The CD4+ T cell count was 148 cells/μL. T-CD4+ lymphopenia is reported to be associated with a risk of PML in patients with SLE (14). We reduced the dose of PSL from 8 to 7 mg and carefully observed the clinical symptoms, MRI findings, and JCV DNA in the CSF. Brain MRI may have shown a slight improvement, and gait disturbance and cognitive disorder were slightly exacerbated over the next four months. Although we detected JCV DNA in the CSF, it did not increase for more than four months.\n\nThe inconsistent detection of JCV DNA in the CSF, atypical brain MRI findings, and the clinical course prevented us from confirming the diagnosis in the present patient. As the treatment for PML is quite different from that for SLE-related vasculitis, it is important to verify the diagnosis. Because SLE-related vasculitis could not be ruled out, a brain biopsy of the corpus callosum (Fig. 1, arrow) was performed. We also examined the nucleotide sequences of the JCV genome in the CSF and brain tissues to clarify whether or not the JCV was PML-type.\n\nPathological detection of JCV-infected glial cells\nSix pieces of fragmented brain tissues, up to approximately 1×5 mm in size, were obtained. In hematoxylin/eosin staining, numerous macrophages were apparent (Fig. 2A), compatible with a demyelinating lesion. Although astroglia with large bizarre nuclei were present (Fig. 2B), oligodendroglia-like cells with typical JCV inclusions were hardly detected. Immunohistochemical labeling of two pieces of brain tissues showed decreased GFAP signals with an elevated number of CD68-positive cells (Fig. 2C and D) in contrast to four other pieces with normal GFAP signals and relatively few CD68-positive cells (Fig. 2E and F). The former two pieces were more severely damaged than the latter four, and atypical astrocytes with bizarre nuclei were present.\n\nFigure 2. Pathology of early PML. A, B: Biopsied brain tissues show atypical astroglia with large irregular nuclei (arrow), but oligodendroglia-like cells with typical JCV inclusions were hardly detectable with Hematoxylin and Eosin staining. C, D: One piece of brain tissue showed decreased GFAP signals with an elevated CD68-positive cell density, suggesting advanced tissue degradation. C: GFAP, D: CD68. E, F: Another piece was rather mildly affected with relatively normal GFAP signals and a lower CD68-positive cell density. E: GFAP, F: CD68. G: Immunohistochemistry (IHC) for JCV capsid proteins. JCV-positive cells were hardly detected with immunohistochemistry, except for one potentially positive cell (inset). H: In situ hybridization (ISH) for JCV DNA. ISH detected more than 20 JCV-positive cells (circled in red), with the largest number of positive cells observed in tissues with higher CD68-positive cell density. I-L: JCV-positive cells with ISH. All cells contained punctate signals in the enlarged nuclei, compatible with clustered JCV virions, represented as dot-shaped inclusions. Scale bars: (A) 200 µm; (B) 50 µm; (C-F) 1 mm; (G, H) 500 µm; (I-L) 25 µm. PML: progressive multifocal leukoencephalopathy, JCV: JC virus\n\nImmunohistochemistry with anti-JCV antibodies (VP1, VP2/VP3C) was performed, and only one potentially JCV-positive cell was detected with the anti-JCV VP1 antibody (Fig. 2G, inset); infected cells were not clearly positive with the anti-JCV VP2/VP3C antibody (data not shown). However, a more sensitive in situ hybridization (ISH) method targeting JCV DNA revealed more than 20 JCV-positive oligodendroglia-like cells. Most JCV-positive cells were present in the two pieces of brain tissue with the higher CD68-positive cell density (Fig. 2H). All JCV-positive cells showed intranuclear punctate signals indicative of clustered JCV progenies at promyelocytic leukemia nuclear bodies (Fig. 2I-L). The host inflammatory response was minimal, and only a few CD3-positive T cells were observed. Nearly equal numbers of CD4- and CD8-positive cells were present. Inflammatory cells of the B-cell lineage were also examined, but immunoreactivity for CD20, CD79a, and CD138 was not detectable (data not shown). These findings argued against SLE-related vasculitis.\n\nThe JCV genome in the CSF and brain tissues was cloned, and the nucleotide sequences were examined. Apparent mutations (deletion and insertions) characteristic of the PML-type virus were found in the non-coding control region (NCCR) (Fig. 3). Based on these pathological findings and the nucleotide sequence analysis, the diagnosis of PML was confirmed.\n\nFigure 3. A comparison of the JCV non-coding control region (NCCR) sequence pattern. The NCCR sequence patterns in the CSF and brain tissues from this patient were compared with the archetype (CY) and PML-type NCCRs (Mad-1). The horizontal gray lines indicate the DNA fragments identical to the archetype NCCR (5' and 3' nucleotide positions 1-267 within the JCV genotype). The black lines indicate the duplicated sequences inserted into the deleted region. The nucleotide numbers corresponding to the archetype NCCR are shown above or below the solid lines. CSF: cerebrospinal fluid, PML: progressive multifocal leukoencephalopathy\n\nClinical course after the brain biopsy\nOnce the diagnosis was confirmed, MMF was gradually tapered off, and mefloquine was administered (loading dose of 275 mg for 3 days, followed by 275 mg once per week). Brain MRI revealed a gradual improvement in the lesions, and no new lesions developed after these therapeutic interventions. The PCR analysis of the CSF was negative for JCV DNA, 7 months after the brain biopsy, and it has been consistently negative for the past 12 months. The number of CD4+ T cells changed slightly, but no definite trend has been observed so far. Cognitive dysfunction improved slightly without ataxic deterioration (Fig. 4). The patient has been stable for over 18 months.\n\nFigure 4. A summary of the clinical course of the diagnostic and therapeutic procedures with corresponding MR images. The timeline shown above represents the clinical course (24 months) after the first visit. Of note, punctate lesions in the deep white matter and internal capsule on FLAIR images gradually disappeared, and no new lesions have developed since the tapering-off of mycophenolate mofetil and the administration of mefloquine. The CSF was negative for JCV DNA at 11 months and has remained negative for the past 12 months. The ataxia has not worsened, and cognitive dysfunction has improved slightly. The patient has been stable for more than 18 months since the brain biopsy. JCV: JC virus, CSF: cerebrospinal fluid, MMSE: Mini Mental State Examination, FLAIR: fluid- attenuated inversion recovery\n\nDiscussion\nRecently, PML development resulting from the use of immunomodulatory drugs has become a serious concern, and JCV in particular is known to reactivate with disease-modifying MS therapies, such as NTZ. The early diagnosis of PML is crucial, and rare MR images of a punctate pattern in the deep white matter have been described as a promising early sign for the diagnosis of NTZ-associated PML (7-10). Contrast enhancement with the punctate pattern may suggest PML-immune reconstitution inflammatory syndrome or productive JCV infection (8, 15). However, whether or not this unique MR pattern is also indicative of PML in non-MS patients has been unclear, and the relevance of this pattern to the underlying histopathology also remains to be elucidated. This is the first case in which a punctate pattern was observed on MRI in a patient with SLE, and an early stage of PML was pathologically proven.\n\nMRI in the present case revealed small, punctate, T2-/FLAIR-hyperintense and T1-hypointense lesions in the bilateral cerebral peduncles, internal capsule, corpus callosum, and deep white matter of the left frontal lobe and bilateral periventricular area. Because these images were completely different from those observed in previously reported PML cases with SLE (5, 16, 17), it was difficult to diagnose this case with PML based on the MRI findings alone, and it was possible to suspect SLE-related vasculitis (11, 12). Although PCR showed that the CSF was positive for JCV DNA (500 copies/mL) at the initial visit, the brain MRI findings and the clinical course were atypical for PML. The commonly used PCR method for detecting JCV DNA targets the large T antigen of JCV and cannot distinguish PML-type JCV from archetype JCV. The CSF of our patient may have contained archetype JCV. Thus, the detection of JCV DNA in the CSF by PCR was not sufficient to establish a definite diagnosis in an atypical case such as this.\n\nIn our patient, punctate MRI lesions were scattered in the vicinity of the larger merged lesion in the left frontal lobe, resembling the “milky way appearance” reportedly observed at the early stages in patients with NTZ-associated PML (8, 18). We therefore considered that this MRI pattern might similarly indicate an early stage of PML in our patient with SLE. However, the atypical clinical course and MRI findings alone were insufficient to confirm the diagnosis. We therefore performed a brain biopsy, resulting in a definite diagnosis of PML. Of note, this unique punctate MRI pattern was observed in a case of non-NTZ-associated PML. Some PML cases in patients with psoriasis were reported to display punctate lesions on MRI, although the MRI findings were not well-described (19, 20). The punctate pattern may not be specific for NTZ-associated PML but instead ubiquitous for PML.\n\nWe first analyzed the pathology of early-stage PML showing a punctate MRI pattern. Despite the presence of relatively large T2-/FLAIR-hyperintense lesions, JCV-infected oligodendroglia-like cells were hardly detected with histological staining and immunolabeling; however, more than 20 JCV-positive cells were detected with sensitive ISH. These data indicate that regardless of the number of JCV-infected cells, the viral replication rate in each cell was relatively low, resulting in only mild tissue degeneration. JCV DNA in the CSF was not always detected in repeated PCR trials, which may indicate low viral replication, consistent with the pathological findings. Biopsied brain tissue specimens are usually tiny, and the JCV-infected oligodendroglia-like cells were scattered in the samples we obtained. Our samples may therefore not have contained any affected lesions simply due to technical limitations. In our patient, one of the biopsied brain tissues fortunately contained a sufficient number of JCV-positive cells to confirm the diagnosis. We cannot deny the possibility that biopsied samples from other areas with strongly hypointense signals on T1-weighted images might have revealed more severe pathological changes with abundant populations of JCV-positive cells. Although early cytopathological changes, including the dot-shaped inclusions in JCV-infected cells, have been studied (3, 21), most of our knowledge about PML pathology is derived from autopsied cases typically associated with HIV infection (22). Thus, the present case is important for its novelty. Furthering our understanding of early PML pathology will aid in the diagnosis of biopsied brain tissues.\n\nWhen the immunosuppressant was tapered off and mefloquine was administered, the T2-/FLAIR-hyperintense lesions gradually diminished in size, and the patient has remained stable over the long term. A punctate MRI pattern is not specific to NTZ-associated PML, and an awareness of this unique MRI pattern will aid in the early diagnosis of PML, leading to the early treatment and a better prognosis.\n\n\nThe treatment with mefloquine was approved by our hospital Ethics Committee. We obtained written informed consent from the patient.\n\nFinancial Support\nThis work was supported in part by JSPS KAKENHI (Grand Number 17K09768 and 15K06759) and by a Grant-in-Aid for the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant Number H29-Nanchitou (Nan)-Ippan-036).\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank Takayuki Funatsu for performing the brain biopsy, Souichi Nukuzuma and Masayuki Saijo for the analysis of JCV in the CSF, and Kenta Takahashi for the analysis of JCV in the biopsied brain tissues.\n==== Refs\n1. \nTan CS , Koralnik IJ \nProgressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis . Lancet Neurol \n9 : 425 -437 , 2010 .20298966 \n2. \nWhite MK , Khalili K \nPathogenesis of progressive multifocal leukoencephalopathy--revisited . J Infect Dis \n203 : 578 -586 , 2011 .21227915 \n3. \nShishido-Hara Y \nProgressive multifocal leukoencephalopathy and promyelocytic leukemia nuclear bodies: a review of clinical, neuropathological, and virological aspects of JC virus-induced demyelinating disease . Acta Neuropathol \n120 : 403 -417 , 2010 .20464404 \n4. \nSchwab N , Schneider-Hohendorf T , Melzer N , Cutter G , Wiendl H \nNatalizumab-associated PML: challenges with incidence, resulting risk, and risk stratification . Neurology \n88 : 1197 -1205 , 2017 .28228564 \n5. \nHenegar CE , Eudy AM , Kharat V , Hill DD , Bennett D , Haight B \nProgressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review . Lupus \n25 : 617 -626 , 2016 .26743322 \n6. \nSahraian MA , Radue EW , Eshaghi A , Besliu S , Minagar A \nProgressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis . Eur J Neurol \n19 : 1060 -1069 , 2012 .22136455 \n7. \nPhan-Ba R , Lommers E , Tshibanda L , et al \nMRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy . J Neurol Neurosurg Psychiatry \n83 : 224 -226 , 2012 .22013244 \n8. \nHodel J , Darchis C , Outteryck O , et al \nPunctate pattern: a promising imaging marker for the diagnosis of natalizumab-associated PML . Neurology \n86 : 1516 -1523 , 2016 .27009257 \n9. \nWijburg MT , Witte BI , Vennegoor A , et al \nMRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance . J Neurol Neurosurg Psychiatry \n87 : 1138 -1145 , 2016 .27530808 \n10. \nHodel J , Outteryck O , Dubron C , et al \nAsymptomatic progressive multifocal leukoencephalopathy associated with natalizumab: diagnostic precision with MR imaging . Radiology \n278 : 863 -872 , 2016 .26436861 \n11. \nBertsias GK , Boumpas DT \nPathogenesis, diagnosis and management of neuropsychiatric SLE manifestations . Nat Rev Rheumatol \n6 : 358 -367 , 2010 .20458332 \n12. \nJennings JE , Sundgren PC , Attwood J , McCune J , Maly P \nValue of MRI of the brain in patients with systemic lupus erythematosus and neurologic disturbance . Neuroradiology \n46 : 15 -21 , 2004 .14648006 \n13. \nPlavina T , Subramanyam M , Bloomgren G , et al \nAnti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy . Ann Neurol \n76 : 802 -812 , 2014 .25273271 \n14. \nBrandao M , Damasio J , Marinho A , et al \nSystemic lupus erythematosus, progressive multifocal leukoencephalopathy, and T-CD4+ lymphopenia . Clin Rev Allergy Immunol \n43 : 302 -307 , 2012 .22674017 \n15. \nWattjes MP , Verhoeff L , Zentjens W , et al \nPunctate lesion pattern suggestive of perivascular inflammation in acute natalizumab-associated progressive multifocal leukoencephalopathy: productive JC virus infection or preclinical PML-IRIS manifestation? \nJ Neurol Neurosurg Psychiatry \n84 : 1176 -1177 , 2013 .23695498 \n16. \nFredericks CA , Kvam KA , Bear J , Crabtree GS , Josephson SA \nA case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab . Lupus \n23 : 711 -713 , 2014 .24531080 \n17. \nBeppu M , Kawamoto M , Nukuzuma S , Kohara N \nMefloquine improved progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus . Intern Med \n51 : 1245 -1247 , 2012 .22687798 \n18. \nSinnecker T , Othman J , Kuhl M , et al \n7T MRI in natalizumab-associated PML and ongoing MS disease activity: a case study . Neurol Neuroimmunol Neuroinflamm \n2 : e171 , 2015 .26568970 \n19. \nGieselbach RJ , Muller-Hansma AH , Wijburg MT , et al \nProgressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases . J Neurol \n264 : 1155 -1164 , 2017 .28536921 \n20. \nBartsch T , Rempe T , Wrede A , et al \nProgressive neurologic dysfunction in a psoriasis patient treated with dimethyl fumarate . Ann Neurol \n78 : 501 -514 , 2015 .26150206 \n21. \nShishido-Hara Y , Yazawa T , Nagane M , et al \nJC virus inclusions in progressive multifocal leukoencephalopathy: scaffolding promyelocytic leukemia nuclear bodies grow with cell cycle transition through an S-to-G2-like state in enlarging oligodendrocyte nuclei . J Neuropathol Exp Neurol \n73 : 442 -453 , 2014 .24709678 \n22. \nBerger JR , Aksamit AJ , Clifford DB , et al \nPML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section . Neurology \n80 : 1430 -1438 , 2013 .23568998\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(18)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "early diagnosis; mefloquine; progressive multifocal leukoencephalopathy (PML); punctate pattern, pathological examination; systemic lupus erythematosus (SLE)", "medline_ta": "Intern Med", "mesh_terms": "D000328:Adult; D001706:Biopsy; D001921:Brain; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D017403:In Situ Hybridization; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008180:Lupus Erythematosus, Systemic; D008279:Magnetic Resonance Imaging; D015767:Mefloquine; D000069442:Natalizumab", "nlm_unique_id": "9204241", "other_id": null, "pages": "2727-2734", "pmc": null, "pmid": "29709947", "pubdate": "2018-09-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20464404;28536921;21227915;28228564;23568998;24531080;27530808;20298966;27009257;26743322;25273271;23695498;14648006;24709678;22687798;22674017;26150206;26436861;26568970;22136455;22013244;20458332", "title": "A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study.", "title_normalized": "a punctate magnetic resonance imaging pattern in a patient with systemic lupus erythematosus is an early sign of progressive multifocal leukoencephalopathy a clinicopathological study" }

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{ "abstract": "Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control.", "affiliations": "Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.;Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan.", "authors": "Furukawa|Sachiko|S|;Oobu|Kazunari|K|;Moriyama|Masafumi|M|;Kawano|Shintaro|S|;Sako|Saori|S|;Hayashida|Jun-Nosuke|JN|;Matsubara|Ryota|R|;Ogata|Ken-Ichi|KI|;Kiyoshima|Tamotsu|T|;Nakamura|Seiji|S|", "chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.8946-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2922524510.2169/internalmedicine.8946-17Case ReportOral Methotrexate-related Lymphoproliferative Disease Presenting with Severe Osteonecrosis of the Jaw: A Case Report and Literature Review Furukawa Sachiko 1Oobu Kazunari 1Moriyama Masafumi 12Kawano Shintaro 1Sako Saori 1Hayashida Jun-Nosuke 1Matsubara Ryota 1Ogata Ken-Ichi 1Kiyoshima Tamotsu 3Nakamura Seiji 1\n1 Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Japan\n2 OBT Research Center, Faculty of Dental Science, Kyushu University, Japan\n3 Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, JapanCorrespondence to Dr.　Kazunari Oobu, [email protected]\n\n8 12 2017 15 2 2018 57 4 575 581 30 1 2017 17 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control. \n\nmethotrexate-related lymphoproliferative disordermedication-related osteonecrosis of the jawrheumatoid arthritislymphomaEpstein-Barr virus\n==== Body\nIntroduction\nMethotrexate (MTX) is the current first-line treatment for rheumatoid arthritis (RA) (1). However, many recent case studies have reported that long-term MTX treatment resulted in MTX-related lymphoproliferative disorder (MTX-LPD) in RA patients (2,3). The recent World Health Organization classification of lymphoid neoplasms categorizes MTX-LPD as an “other iatrogenic immunodeficiency-associated LPD” (4). MTX-LPD may resolve several weeks after the withdrawal of MTX therapy; however, additional treatments, such as chemotherapy and radiotherapy, should be considered for patients with persistent LPD after MTX withdrawal (5-7). Regarding the mechanism underlying the onset of MTX-LPD, it is considered that immunosuppression by MTX reduces the host immunosurveillance of Epstein-Barr virus (EBV)-infected B cells, because approximately 50% of patients with MTX-LPD are EBV-positive (8).\n\nBisphosphonates (BPs) are the primary treatment for osteoporosis, bone metastasis, hypercalcemia caused by malignancies, Paget disease of bone, and osteolytic lesions of multiple myeloma. Although BP treatment has many benefits for patients with skeletal complications, it is associated with a number of adverse effects, the most important of which is BP-related osteonecrosis of the jaw (BRONJ) (9,10). Since BRONJ was first reported in 2003, many additional cases have been reported (11,12). Because osteonecrosis of the jaw can also be caused by other drugs, the American Association of Oral and Maxillofacial Surgery updated their position paper on BRONJ in 2014. The term BRONJ was replaced with medication-related osteonecrosis of the jaw (MRONJ) (13). The clinical manifestations of MRONJ include soft tissue swelling, fistula, abscess, pain, and bone exposure (14). There is currently no gold standard for the treatment of MRONJ or MTX-LPD. MTX-LPD generally develops at extra-nodal sites (8). To the best of our knowledge MTX-LPD of the oral cavity is rare, and no previous studies have reported the serial treatment of MTX-LPD with MRONJ.\n\nWe herein describe a case of MTX-LPD with MRONJ. In addition, we performed a systematic literature review to identify all cases of MTX-LPD of the oral cavity, to investigate the characteristics of oral MTX-LPD.\n\nCase Report\nIn July 2015, an 81-year-old Japanese woman was referred to the Department of Oral Surgery at Kyushu University Hospital for the evaluation of upper left mandible pain. In 2009, the patient was diagnosed with RA based on the findings of bone destruction and swelling at her wrists and a positive serum test for rheumatoid factor. She had been taking BP (BonalonⓇ; 35 mg/week) and prednisolone (PrednisolonⓇ; 5 mg/day) for 7 years and MTX (MetolateⓇ; 8 mg/week) for 4 years. In April 2015, she fell while walking on stairs and noticed slight bleeding near her left first molar. Two weeks earlier she visited another dentist due to continuous pain of the left maxillary gingiva that had persisted for 2 months. The dentist suspected MRONJ based on the exposure of the maxillary bone.\n\nOur initial examination revealed an ulcer with induration on the buccal gingiva, near the upper left molar, which was mobile (Fig. 1A). Radiography showed left sinusitis and the loss of vertical bone near the upper left molars (Fig. 1B). These findings suggested gingival carcinoma or lymphoma. A cytological analysis of the ulcerative gingiva revealed class III cytology accompanied by numerous atypical lymphocytes; however, these findings were not conclusive for malignancy. The results of serological tests were unremarkable; however, the patient's C-reactive protein concentration was slightly elevated (0.64 mg/dL). Coronal computed tomography revealed a lesion arising from the upper left second premolar to the left sinus and the destruction of the buccal cortical bone in the left posterior maxilla (Fig. 2A). 18Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) was performed to evaluate the extent of the primary lesion, the status of the regional lymph nodes, and the possibility of distant metastasis. The images showed the abnormal accumulation of FDG in the left upper maxilla and sinus (maximum standardized uptake value, 4.94) and no accumulation in several systemic lymph nodes or other lesions (Fig. 2B). These findings indicated that the lesion was malignant or another type of tumor. She was immediately referred to the hematology department of our hospital and an incisional biopsy of the upper left region was performed. Immunophenotyping of the upper left gingiva gated by CD45+ cells yielded the following findings: CD3+ CD20-, 48.3%; CD3- CD20+, 14.6%; natural killer cells, 30.5%; CD19+, 17.7%; κ chain, 4.25%; and λ chain, 3.72%. These findings were not conclusive for a diagnosis of any type of malignant lymphoma. A pathological analysis showed the infiltration of numerous lymphocytes and the diffuse proliferation of medium- to large-sized atypical lymphoid cells with large nuclei and clumped chromatin. Moreover, an immunohistochemical analysis revealed extensive lymphocytic infiltration. The cells were mostly B cells (positive for CD20 and CD79a); however a few T cells were found to be CD3-positive. The additional performance of in situ hybridization to detect EBV-encoded RNA (15) showed the strong infiltration of EBV-positive atypical lymphoid cells (Fig. 3). In sum, these findings confirmed a diagnosis of EBV-positive diffuse large B-cell lymphoma (DLBCL). Based on the pathological and clinical findings, the patient was diagnosed with MTX-LPD, and MTX therapy was immediately stopped (Fig. 4A-a). To control RA, the patient was treated with prednisolone (3 mg/day). We continued to monitor the patient carefully during the initial 2-week cessation of MTX. The exposed bone was rinsed three times a week with 0.05% glucuronic acid chlorhexidine solution, and the necrotic gingiva and induration gradually disappeared (Fig. 4A-b). At four months after the withdrawal of MTX and rinsing with glucuronic acid chlorhexidine solution, the upper left molars were easily extracted, along with the surrounding floating bone (Fig. 4A-c). The necrotic and indurated tissue had disappeared, and no other adverse events were noted (Fig. 4A-d). CT images obtained at 4 and 7 months after the withdrawal of MTX showed the improvement of the left sinusitis and the absence of inflammation or floating bone in the maxilla (Fig. 4B). No inflammation was observed near the upper left gingiva during this period, and the patient did not require antibiotic treatment. There was no recurrence of MTX-LPD or extra-nodal lymphoma, and her RA remained well controlled at 1 year after the discontinuation of MTX treatment.\n\nFigure 1. A photograph and photoradiograph obtained at the first examination. (A) The exposure of the buccal and palate bone, and the buccal root of the molars were noted (mirror reflection). The upper-left first and second molars showed deflection. (B) The left sinus had a cloudy appearance (yellow arrowhead).\n\nFigure 2. Computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET). (A) CT revealed a mass around the upper-left maxilla. (B) FDG-PET indicated abnormal accumulation in the upper-left gingiva.\n\nFigure 3. The histological and immunohistochemical findings of the upper-left gingiva. Hematoxylin and Eosin staining (a). Immunohistochemical staining for CD20 (b), CD79a (c), CD3 (d), and Epstein-Barr encoding region (EBER) (e). Scale bars: 100 μm.\n\nFigure 4. Photographs and photoradiographs obtained after the withdrawal of methotrexate (MTX). (A) Photographs of the upper-left maxilla at 0 days (a), 2 weeks (b), 4 months (c), and 7 months (d). All of the photographs show mirror reflections. (B) CT images obtained after the withdrawal of MTX for 4 months (a, b) and 7 months (c, d).\n\nDiscussion\nEvidence from numerous reports indicates that the risk of LPD in RA (RA-LPD) patients is 2.0-5.5 times that of the general population (16). The underlying mechanism is unclear; however, patients with RA have persistent immunological abnormalities that may lead to clonal selection, which can result in the malignant transformation of B cells, the decreased apoptosis of infected B cells, reduced natural killer cell activity, the proliferation of latent EBV infection, and direct oncogenic action. All of these conditions may be potentiated by immunomodulation therapies. The number of reported LPD cases has been increasing among patients with RA receiving MTX, a condition referred to as MTX-LPD (8). The characteristics of MTX-LPD are as follows: (1) the most frequent subtype of MTX-LPD is DLBCL rather than Hodgkin lymphoma or Hodgkin disease-like lymphoma, (2) the frequency of EBV-positive case is higher in MTX-LPD than in RA-LPD or age-related LPD, (3) the possibility of improvement is high (20-60%), but only when MTX is withdrawn for several weeks, (4) the frequency of extra-nodal lymphoma is higher in MTX-LPD cases than in RA-LPD or age-related LPD cases, and (5) the duration to the outcome is shorter in patients with MTX-LPD than in those with RA-LPD (17,18). In approximately 40-50% of cases, MTX-LPD develops at extra-nodal sites, such as the skin, lung, liver, gastrointestinal tract, and kidney (8).\n\nA review of the literature revealed only 19 cases of oral MTX-LPD, including our 3 cases (Table 1) (7,19-30). At the time of the diagnosis of MTX-LPD, the mean age of the patients was 71.1 years (range, 44-87 years) and the male-to-female ratio was 4:15 (the male-to-female ratio in RA was 1:4). The mean duration of MTX treatment was 6.6 years (range, 0.1-20 years). The frequency of bone exposure and DLBCL was 56.2% (9/16), the frequency of EBV positivity was 100.0% (13/13), and MTX-LPD resolved in 80.0% (12/15) of patients after the discontinuation of MTX. The data on the mean age, sex ratio, and the duration of MTX treatment were similar to those of previous reports on oral MTX-LPD. In contrast, the frequency of DLBCL and EBV-positivity in the patients with oral MTX-LPD were higher in comparison to previous reports on non-oral MTX-LPD, as summarized in Table 2 (6,21,24,31). Some reports have suggested that spontaneous remission occurs due to the withdrawal of MTX and noted an association between EBV positivity and the spontaneous remission of MTX-LPD (32). The initial symptoms of oral MTX-LPD included ulcer (80.0%, 12/15) and swelling (20.0%, 3/15), and the main sites affected included the gingiva (66.7%, 12/18), the hard palate (11.1%, 2/18) and the buccal mucosa (11.1%, 2/18). Other regions of the oral cavity, including the tongue, soft palate, sinus, and lip, can also be target organs because EBV in the head and neck region, including the pharynx and the salivary glands, generally remains dormant. Dentists and clinicians should bear in mind that MTX-LPD can be observed in any lesion.\n\nTable 1. Clinicopathological Findings of 19 Cases with Oral Methotrexate-related Lymphoproligeractive Disorders (MTX-LPD).\n\nNo.\tAge\tSex\tLesion\tComplaining\tMTX intake (y)\tHistology\tEBV\tBP intake (y)\tBone Exposure\tMTX withdrawal\tRecurrence\tChemotherapy\tReference\t\n1.\t72\tF\tgingiva\tulcer\tNA\tpoly-B cell lymphoma\t+\tNA\t+\t+\t-\t-\t(19)\t\n2.\t69\tF\tgingiva\tulcer\tNA\tWegener’s lymphoma\tNA\tNA\t+\t+\t-\t-\t(19)\t\n3.\t73\tF\toral cavity\tNA\t2\tperipheral T cell lymphoma\tNA\t-\t-\t+\t-\t-\t(21)\t\n4.\t73\tF\toral cavity\tNA\t2\tDLBCL\tLMP-1\t-\t+\t+\t-\t-\t(20)\t\n5.\t70\tF\tpalate\tulcer\t6\tDLBCL\tEBNA2\t-\t-\t+\t-\t-\t(7)\t\n6.\t69\tF\tgingiva\tNA\tNA\tHodgkin\tLMP-1\t-\tNA\t+\tNA\tNA\t(22)\t\n7.\t80\tM\ttongue\tulcer\tNA\tNA\tNA\tNA\t-\tNA\tNA\tNA\t(30)\t\n8.\t76\tF\tgingiva\tulcer, bleeding\t10\tDLBCL\tEBER\t-\t-\t+\t+\tR-THP-COP\t(24)\t\n9.\t67\tF\tpalate\tulcer\t9\tDLBCL\tEBER\t9\t+\t+\t-\t-\t(25)\t\n10.\t75\tF\tgingiva\tswelling\t5\tDLBCL\tEBER\tNA\t+\t+\t+\tR-CHOP\t(26)\t\n11.\t60\tM\tgingiva\tswelling\t20\tDLBCL\tEBER\t-\t+\t+\t-\t-\t(27)\t\n12.\t71\tF\tbuccal mucosa\tulcer\t0.1\tNA\tNA\t+\t-\t+\t-\t-\t(28)\t\n13.\t87\tF\tbuccal mucosa\tulcer\t2\tNA\tNA\t+\t-\t+\t-\t-\t(28)\t\n14.\t66\tF\tgingiva\tulcer\t3\tDLBCL\tNA\t8M\t+\t+\t-\t-\t(29)\t\n15.\t76\tF\tgingiva\tNA\tNA\tHodgkin\tLMP-1\tNA\tNA\t+\tNA\tNA\t(23)\t\n16.\t67\tM\tpalate\tNA\tNA\tNA\tLMP-1\tNA\tNA\t+\tNA\tNA\t(23)\t\n17.\t81\tF\tgingiva\tulcer\t4\tDLBCL\tEBER\t7\t+\t+\t-\t-\tThis case\t\n18.\t71\tF\tgingiva\tulcer\tNA\tBL\tEBER\t+\t+\t+\t-\t-\tour cases\t\n19.\t77\tF\tgingiva\tulcer\t12\tDLBCL\tEBER\t+\t+\t+\t+\tR-CHOP\t\nMTX: methotrexate, EBV: Epstein-Barr Virus, DLBCL: diffuse large B-cell lymphoma, LMP: latent infection membrane protein, EBNA: EBV nuclear antigen, EBER: Epstein-Barr encording region, R-THP-COP: rituximab, pinorubin, oncovin, endoxan, and prednisolone, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, +: positive, −: negative, NA: not available\n\nTable 2. Comparison of Clinicopathological Findings between Oral and Non-oral MTX-LPD.\n\n\tOral MTX (n=17)\tNon-oral MTX (n=52)\t\nMean age (years)\t71.1\t63.0-69.0\t\nSex (male : female)\t4:13\t20:32\t\nAffected regions\tgingiva, palate, buccal mucosa, tongue\tlymph node, spleen, lung, skin, liver, pleura, kidney, small bowel, breast, neck, thymus, stomach, heart\t\nDuration of MTX treatment (years)\t6.6\t3.1-5.8\t\nDLBCL (%)\t56.2\t30.8-55.3\t\nEBV-positive (%)\t100\t50.0-62.8\t\nReference\tTable 1\t(7), (21), (32)\t\nMTX-LPD: methotrexate- related lymphoproliferative disorder, DLBCL: diffuse large B-cell lymphoma, EBV: Epstein-Barr virus\n\nOur patient had been treated with BPs for 9 years and MTX for 4 years. A diminished CTL function caused by the immunosuppressive effect of MTX permits the reactivation of EBV and the monoclonal proliferation of EBV-infected B cells in the buccal gingiva. Since the gingiva has a unique environment, characterized by its direct contact with the alveolar bone through the periodontal pocket, patients with LPD affecting the cervical gingiva are prone to develop bone exposure, and those who are treated with BPs may subsequently develop necrosis of the alveolar bone.\n\nRecently, EBV-positive mucocutaneous ulcer (EBV-MCU) was proposed as a novel clinical entity that presents as mucocutaneous ulcers of the oropharynx, gastrointestinal tract, or skin, which are caused by latent EBV infection. Iatrogenic immunosuppression for autoimmune disease and age-related immunosenescence have been implicated as risk factors (30).The clinical conditions of this case might be close to those of EBV-MCU.\n\nThe presence of ulcer and adjacent bone exposure in the gingiva complicated the initial diagnosis because the common manifestations of MRONJ include ulcer, swelling, fistula, abscess, and bone exposure. However, our patient also exhibited the progression of ulceration and induration. We therefore performed an incisional biopsy as soon as we suspected malignancy or another tumor. After the diagnosis was confirmed, MRONJ was treated by daily cleaning around the site of bone necrosis with glucuronic acid chlorhexidine solution. After this, the floating necrotic bone and molars gradually resolved. The gingival ulceration and induration resolved in association with bone removal. No guidelines have been established for the treatment of MTX-LPD; however, pathological and immunological examinations are necessary in the selection of treatment.\n\nWe described a case of MTX-LPD with severe MRONJ and the effects of treatment after MTX withdrawal. Many previous case reports have described gingival ulcers or swelling near the sites of osteonecrosis; however, no previous reports have described the treatment of MRONJ or differentiation between MRONJ and MTX-LPD with MRONJ. The present case and the associated review of the literature on oral MTX-LPD suggest that oral MTX-LPD will continue to be a concern because RA patients are increasingly treated with MTX and BPs. Despite the risk of severe adverse effects, MTX is the treatment of choice for RA. Clinicians should bear in mind that oral MTX-LPD is occasionally complicated by MRONJ, and that a pathological examination (e.g., an incisional biopsy and immunohistological examination) is required for the final diagnosis. 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Br J Oral Maxillofac Surg \n54 : 114 -115 , 2016 .\n30. \nDojcinov SD , Venkataraman G , Raffeld M , Pittaluga S , Jaffe ES \nEBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression . Am J Surg Pathol \n34 : 405 -417 , 2010 .20154586 \n31. \nYoshida Y , Takahashi Y , Yamashita H , Kano T , Kaneko H , Mimori A \nClinical characteristics and incidence of methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis . Mod Rheumatol \n24 : 763 -765 , 2014 .24498893 \n32. \nWeiss LM , Chen YY , Liu XF , Shibata D \nEpstein-Barr virus and Hodgkin's disease. A correlative in situ hybridization and polymerase chain reaction study . Am J Pathol \n139 : 1259 -1265 , 1991 .1661073\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(4)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "Epstein-Barr virus; lymphoma; medication-related osteonecrosis of the jaw; methotrexate-related lymphoproliferative disorder; rheumatoid arthritis", "medline_ta": "Intern Med", "mesh_terms": "D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D005260:Female; D006801:Humans; D007568:Jaw; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D010020:Osteonecrosis; D012720:Severity of Illness Index", "nlm_unique_id": "9204241", "other_id": null, "pages": "575-581", "pmc": null, "pmid": "29225245", "pubdate": "2018-02-15", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "24498893;11054684;18167381;8026822;16859835;23560463;17117491;24400722;24811204;25234529;26608686;18461290;25302816;18670155;25834572;23728424;25319961;8656264;17307580;1661073;18571037;20676828;20154586;7674250;9044507;26468825;24133604;15953917;10451061", "title": "Oral Methotrexate-related Lymphoproliferative Disease Presenting with Severe Osteonecrosis of the Jaw: A Case Report and Literature Review.", "title_normalized": "oral methotrexate related lymphoproliferative disease presenting with severe osteonecrosis of the jaw a case report and literature review" }

[ { "companynumb": "JP-CIPLA LTD.-2018JP11601", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "35 MG, PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "35", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG, PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus associated lymphoproliferative disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FURUKAWA S, OOBU K, MORIYAMA M, KAWANO S, SAKO S, HAYASHIDA JN ET AL. ORAL METHOTREXATE-RELATED LYMPHOPROLIFERATIVE DISEASE PRESENTING WITH SEVERE OSTEONECROSIS OF THE JAW: A CASE REPORT AND LITERATURE REVIEW. INTERNAL MEDICINE. 2018?57(4):575 TO 581", "literaturereference_normalized": "oral methotrexate related lymphoproliferative disease presenting with severe osteonecrosis of the jaw a case report and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180316", "receivedate": "20180316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14645712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "We report a case of a 60-year-old man who was referred to a palliative care clinic with monoclonal gammopathy of undetermined significance (MGUS)-associated neuropathy, responding to a therapeutic trial of warfarin. Electromyography showed distal symmetric sensory axonal neuropathy. The patient reported having had improvement of his neuropathic symptoms while taking warfarin postoperatively for thromboprophylaxis 1 year prior, and recurrence of his symptoms after the warfarin was discontinued. The patient was rechallenged with a trial of warfarin, targeting an international normalised ratio of 1.5-2.0. His pain scores decreased from 5/10 to 3/10 at 1 month and symptom improvement was maintained through 24 months of follow-up. Warfarin had a remarkable impact on our patient's symptoms and quality of life. The mechanisms mediating the symptomatic benefit with warfarin are unclear; however, a placebo effect is unlikely. Further studies may help guide the use of warfarin for MGUS-associated neuropathy.", "affiliations": "Division of Palliative Care, Greenville Health System, Greenville, South Carolina, USA.;Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University Health System, Richmond, Virginia, USA.;Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University Health System, Richmond, Virginia, USA.;Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University Health System, Richmond, Virginia, USA.", "authors": "Henry Gomez|Teny|T|;Holkova|Beata|B|;Noreika|Danielle|D|;Del Fabbro|Egidio|E|", "chemical_list": "D000925:Anticoagulants; D014859:Warfarin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2016()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000925:Anticoagulants; D006801:Humans; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance; D010523:Peripheral Nervous System Diseases; D016896:Treatment Outcome; D014859:Warfarin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "27317760", "pubdate": "2016-06-17", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12780789;18796075;7820574;8894407;8909434;9040714;1379409;11911978;23114670;12473754;645746;10540371;10639604;6253529;8383189;18559977;17253554;20175830;16571879;10209166;11325029;23255326;9406596;22516728", "title": "Warfarin improves neuropathy in monoclonal gammopathy of undetermined significance.", "title_normalized": "warfarin improves neuropathy in monoclonal gammopathy of undetermined significance" }

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{ "abstract": "BACKGROUND\nThe safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown.\n\n\nMETHODS\nWe describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen.\n\n\nCONCLUSIONS\nBecause of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.", "affiliations": "Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Department of Pathology, Faculty of Medicine, Saga University Hospital, Saga, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan.;Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan. [email protected].", "authors": "Hirakawa|Haruki|H|;Nakashima|Chiho|C|;Nakamura|Tomomi|T|;Masuda|Masanori|M|;Funakoshi|Taro|T|;Nakagawa|Shunsaku|S|;Horimatsu|Takahiro|T|;Matsubara|Kazuo|K|;Muto|Manabu|M|;Kimura|Shinya|S|;Sueoka-Aragane|Naoko|N|", "chemical_list": "D000970:Antineoplastic Agents; D005047:Etoposide; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1186/s13256-017-1213-7", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 121310.1186/s13256-017-1213-7Case ReportChemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report Hirakawa Haruki [email protected] 1Nakashima Chiho [email protected] 1Nakamura Tomomi [email protected] 1Masuda Masanori [email protected] 2Funakoshi Taro [email protected] 3Nakagawa Shunsaku [email protected] 4Horimatsu Takahiro [email protected] 3Matsubara Kazuo [email protected] 4Muto Manabu [email protected] 3Kimura Shinya [email protected] 1Sueoka-Aragane Naoko [email protected] 11 0000 0001 1172 4459grid.412339.eDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Naoko Sueoka-Aragane, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan 2 grid.416518.fDepartment of Pathology, Faculty of Medicine, Saga University Hospital, Saga, Japan 3 0000 0004 0372 2033grid.258799.8Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4 0000 0004 0531 2775grid.411217.0Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan 16 2 2017 16 2 2017 2017 11 434 10 2016 17 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown.\n\nCase presentation\nWe describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen.\n\nConclusions\nBecause of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.\n\nKeywords\nMediastinal yolk sac tumorHemodialysisRenal insufficiencyCisplatinPharmacokineticsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nGerm cell tumors of extragonadal origin have been reported to make up from 1 to 5% of all germ cell tumors. The most common site is the mediastinum, constituting 50 to 70% [1, 2]. In general, germ cell tumors are sensitive to platinum-based chemotherapy and patients have a favorable prognosis. However, response of mediastinal non-seminomatous germ cell tumors to therapy is less than favorable, so these tumors have been classified into the poor prognosis group [3, 4]. It has been reported that 40 to 54% of patients with mediastinal non-seminomatous germ cell tumor treated with platinum-based chemotherapy followed by surgical resection achieved long-term disease-free survival, but patients who relapsed after initial treatment experienced dismal outcomes with only 10% long-term survival [5–7]. Therefore, it is important to accomplish successful initial chemotherapy with an adequate dose.\n\nRecently, the number of patients with end-stage renal failure undergoing hemodialysis (HD) is increasing, and patients undergoing HD are potentially at high risk of cancer [8]. However, the safety and efficacy of chemotherapy for patients undergoing concomitant HD have not been fully established and optimal doses of anti-cancer drugs and best timing of HD remains unclear. Many patients with cancer undergoing HD might be under-treated because the pharmacokinetics (PK) of anti-cancer drugs in such patients remains unknown and severe adverse effects are feared. However, chemosensitive cancers such as germ cell tumors treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect.\n\nIn this article, we report the case of a patient with mediastinal yolk sac tumor who was successfully treated with cisplatin and etoposide while concomitantly undergoing HD. We carried out a PK analysis of cisplatin as part of a multicenter study and carefully considered the relationship between adverse effects and blood concentration of cisplatin.\n\nCase presentation\nA 31-year-old Japanese man was referred to our hospital with renal dysfunction in April 2014. He had a history of hypertension, hyperuricemia, and pituitary dwarfism, but had not taken any medications. He was 159.4 cm in height and 42.6 kg in weight (body surface area 1.398 m2). Initial blood tests showed anemia and renal dysfunction: blood urea nitrogen (BUN) 64.6 mg/dl, creatinine (Cr) 5.66 mg/dl. A chest X-ray performed to evaluate cardiomegaly revealed a mediastinal tumor in his right thorax; a computed tomography (CT) scan confirmed the mass to be a well-defined, homogeneous solid tumor (53×35 mm) in his anterior mediastinum (Fig. 1). An additional blood examination showed a high level, 322.6 ng/ml, of alpha-fetoprotein (AFP, normal <9 ng/ml), but his beta-human chorionic gonadotropin (β-hCG) level was within normal range. A CT-guided biopsy of the mediastinal tumor showed the presence of tumor cells with mixed sinusoidal-like, cystic, and papillary structures (Fig. 2a) and Schiller–Duval body (Fig. 2b), which was positive by immunohistochemistry (IHC) for cytokeratin (CK) AE1/AE3 and AFP, and negative for placental alkaline phosphatase (PLAP), β-hCG, and CD30 (Fig. 2c, d), resulting in a diagnosis of primary mediastinal yolk sac tumor. Because of the complication of end-stage renal insufficiency, surgery was selected as the first treatment; following surgery, his AFP level decreased to the normal range. Subsequently, chemotherapy with cisplatin (10 mg/m2) and etoposide (60 mg/m2) was conducted daily from day 1 through to day 5. HD was started 1 hour after infusions of these agents. Appendicitis with grade 4 neutropenia occurred, so an appendectomy was performed after the first cycle. In addition, grade 3 anemia and grade 4 neutropenia appeared under prophylactic treatment with granulocyte-colony stimulating factor (G-CSF). Because severe hematological toxicities occurred, we conducted chemotherapy without dose escalation on the second cycle. In contrast to the first cycle, toxicities were admissible with 10 mg/m2 cisplatin and 60 mg/m2 etoposide in the second cycle. To elevate the dose intensity, the doses were escalated from the third to the fifth cycles: cisplatin to 15 mg/m2 and etoposide to 75 mg/m2. Grade 4 neutropenia and thrombocytopenia as well as grade 3 anemia were sustained over 7 days in spite of prophylactic treatment with G-CSF. After five cycles of chemotherapy, his AFP level remained in the normal range and there has been no recurrence for 1 year.Fig. 1 Computed tomography scan confirms a solid tumor (53×35 mm) in the anterior mediastinum (arrow)\n\n\nFig. 2 Pathological findings of computed tomography-guided biopsy specimen. a Tumor cells with mixed sinusoidal-like, cystic, and papillary structures were observed (hematoxylin and eosin staining, ×20). b Schiller–Duval body was highlighted with white arrow (hematoxylin and eosin staining, ×100). Immunohistochemical staining is positive for cytokeratin AE1/AE3 (×200) (c) and alpha-fetoprotein (d) (×200)\n\n\n\n\nDuring the third and fourth cycles, free cisplatin blood concentrations were measured as part of a multicenter study. Venous blood samples were collected five times each day: (1) before cisplatin infusion, (2) immediately after infusion, (3) before HD, (4) after HD, and (5) 4 hours after HD on days 1 to 5. In addition, blood was collected before HD on day 8 once in each course (Fig. 3). The time-concentration curve in the third cycle is shown in Fig. 4. Our patient was administered 15 mg/m2 cisplatin, and maximum concentration (Cmax) of free cisplatin was 0.8 to 0.9 μg/mL. Just before treatment with cisplatin, the concentration had not recovered to the level observed after the previous HD. The concentration before infusion of cisplatin gradually increased each day during the 5 days of treatment, and this phenomenon was observed until 8 days after the start of chemotherapy. During the fourth cycle, chemotherapy was administered using the same doses used in the third cycle, and PK was similar to that of the third cycle.Fig. 3 Schedule of chemotherapy, hemodialysis, and blood sampling. In the third and fourth chemotherapy cycles, cisplatin (15 mg/m2) and etoposide (75 mg/m2) was conducted daily from day 1 through to day 5. Hemodialysis was started 1 hour after infusions of these agents. Venous blood samples were collected five times each day: (1) before cisplatin infusion, (2) immediately after infusion, (3) before hemodialysis, (4) after hemodialysis, and (5) 4 hours after hemodialysis on days 1 to 5. In addition, blood was collected (6) before hemodialysis on day 8 once in each course. CDDP cisplatin, ETP etoposide, HD hemodialysis\n\n\nFig. 4 Free cisplatin concentration analysis. The solid and dotted lines show plasma free cisplatin concentration in the third and fourth chemotherapy cycles, respectively. White arrows indicate cisplatin (15 mg/m2) infusions and black two-headed arrows indicate hemodialysis during days 1 to 5. HD hemodialysis\n\n\n\n\nDiscussion\nIn the International Germ Cell Consensus Classification (IGCCC), primary mediastinal yolk sac tumor is classified into the poor prognosis group, and standard treatment consists of induction chemotherapy such as BEP (bleomycin, etoposide, and cisplatin) or VIP (ifosfamide, etoposide, and cisplatin) regimens followed by radical operation [4]. In our case, it was considered likely that standard chemotherapy would not be efficacious because of end-stage renal insufficiency, so surgery was selected as the first treatment so as not to miss the opportunity for complete tumor resection. In addition, bleomycin and active metabolite of ifosfamide are known not to be sufficiently removed by HD, resulting in enhanced toxicities such as pulmonary fibrosis, disturbance of consciousness, and convulsions [9–14]. Therefore, we selected combination chemotherapy with cisplatin and etoposide, and doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through 5 according to previous reports, and the doses were subsequently escalated to 75% with both agents [14]. However, the rationale for using these dosages, especially that of cisplatin, has not been elucidated because of a paucity of PK studies involving patients with HD. Froehner et al. reported that they started the treatment from 50% reduction of cisplatin according to guidelines on testicular cancer, and then escalated to 100% of standard dose after monitoring adverse effects [14].\n\nIn this case, we obtained PK results for cisplatin during cycles 3 and 4 in cooperation with Kyoto University. The findings are as follows, compared with patients with normal renal function administered 100% standard doses of cisplatin [15]: (1) the Cmax of free cisplatin was higher, and (2) concentration gradually increased after HD up to the subsequent infusion of cisplatin (Fig. 4). The higher Cmax might be related to our patient’s low volume of distribution caused by pituitary dwarfism rather than renal insufficiency. Immediately after HD, the concentrations were lower, equivalent to those in patients with normal renal function based on previous reports [15]. However, his free cisplatin concentration rose 4 hours after HD, and gradual accumulation of free cisplatin was observed up until the subsequent treatment with cisplatin. Pronounced elevation of free cisplatin concentration may be due to redistribution from peripheral tissues and reduced excretion of free cisplatin, resulting in an elevated area under the curve (AUC) of free cisplatin leading to severe hematological toxicity [15–18]. Although nephrotoxicity has not been thought to be a limitation in HD patients, dose-related adverse effects are often observed [19], and dose reduction is inevitable just as in our case. Because of the altered PK pharmacodynamics (PD) status of patients with renal dysfunction undergoing HD, determination of cisplatin dosage should be based on monitored concentration to conduct effective and safe chemotherapy.\n\nConclusions\nMalignancies sensitive to chemotherapy require careful maintenance of dose intensity, but this should be performed safely. PK analysis is deemed to be useful for appropriate chemotherapy in patients undergoing HD. Additional evidence from other similar patients is needed to establish suitable chemotherapy regimens for patients with concomitant renal insufficiency.\n\nAbbreviations\nAFPAlpha-fetoprotein\n\nAUCArea under the curve\n\nBEPBleomycin, etoposide, and cisplatin\n\nβ-hCGBeta-human chorionic gonadotropin\n\nBUNBlood urea nitrogen\n\nCKCytokeratin\n\nCmaxMaximum concentration\n\nCrCreatinine\n\nCTComputed tomography\n\nG-CSFGranulocyte-colony stimulating factor\n\nHDHemodialysis\n\nIGCCCInternational Germ Cell Consensus Classification\n\nIHCImmunohistochemistry\n\nPDPharmacodynamics\n\nPKPharmacokinetics\n\nPLAPPlacental alkaline phosphatase\n\nVIPIfosfamide, etoposide, and cisplatin\n\nAcknowledgements\nWe wish to thank our patient and his parents for consenting to the publication of this case report.\n\nFunding\nThere is no financial support for this case report.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nHH, CN, TN, SK, and NSA contributed to patient treatment and collection of venous blood samples for PK PD analysis. MMa contributed to pathological diagnosis. TF, SN, TH, KM, and MMu contributed measurement of free cisplatin blood concentration and PK PD analysis. All authors read and approved the final manuscript. \n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nThe protocol of this multicenter study was approved by the Clinical Research Ethics Committees of Saga University. This patient gave informed consent for blood collection and PK PD analysis according to the Declaration of Helsinki.\n==== Refs\nReferences\n1. McKenney JK Heerema-McKenney A Rouse RV Extragonadal germ cell tumors: a review with emphasis on pathologic features, clinical prognostic variables, and differential diagnostic considerations Adv Anat Pathol. 2007 14 69 92 10.1097/PAP.0b013e31803240e6 17471115 \n2. Dehner LP Germ cell tumors of the mediastinum. Germ cell tumors of the mediastinum Semin Diagn Pathol 1990 7 266 84 2178277 \n3. International Germ Cell Cancer Collaborative Group International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers J Clin Oncol 1997 15 594 603 9053482 \n4. Schmoll HJ Souchon R Krege S Albers P Beyer J Kollmannsberger C European Germ Cell Cancer Consensus Group European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG) Ann Oncol 2004 15 1377 99 10.1093/annonc/mdh301 15319245 \n5. Albany C Einhorn LH Extragonadal germ cell tumors: clinical presentation and management Curr Opin Oncol. 2013 25 261 5 23422328 \n6. Bokemeyer C Nichols CR Droz JP Schmoll HJ Horwich A Gerl A Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis J Clin Oncol. 2002 20 1864 73 10.1200/JCO.2002.07.062 11919246 \n7. Rodney AJ Tannir NM Siefker-Radtke AO Liu P Walsh GL Millikan RE Survival outcomes for men with mediastinal germ-cell tumors: the University of Texas M. D. Anderson Cancer Center experience Urol Oncol 2012 30 879 85 10.1016/j.urolonc.2010.08.005 20933444 \n8. Maisonneuve P Agodoa L Gellert R Stewart JH Buccianti G Lowenfels AB Cancer in patients on dialysis for end-stage renal disease: an international collaborative study Lancet. 1999 354 93 9 10.1016/S0140-6736(99)06154-1 10408483 \n9. Superfin D Iannucci AA Davies AM Commentary: Oncologic drugs in patients with organ dysfunction: a summary Oncologist. 2007 12 1070 83 10.1634/theoncologist.12-9-1070 17914077 \n10. Eneman JD Philips GK Cancer management in patients with end-stage renal disease Oncology (Williston Park) 2005 19 1199 214 16255135 \n11. Crooke ST Luft F Broughton A Strong J Casson K Einhorn L Bleomycin serum pharmacokinetics as determined by a radioimmunoassay and a microbiologic assay in a patient with compromised renal function Cancer. 1977 39 1430 4 10.1002/1097-0142(197704)39:4<1430::AID-CNCR2820390412>3.0.CO;2-V 66973 \n12. Tomita M Aoki Y Tanaka K Effect of haemodialysis on the pharmacokinetics of antineoplastic drugs Clin Pharmacokinet. 2004 43 515 27 10.2165/00003088-200443080-00002 15170366 \n13. Carlson L Goren MP Bush DA Griener JC Quigley R Tkaczewski I Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms’ tumor Cancer Chemother Pharmacol. 1998 41 140 6 10.1007/s002800050720 9443627 \n14. Froehner M Passauer J Schuler U Hakenberg OW Wirth MP Successful chemotherapy for advanced nonseminomatous germ-cell tumor in a patient undergoing chronic hemodialysis J Clin Oncol. 2007 10 1282 4 10.1200/JCO.2006.09.9549 \n15. Ikeda K Terashima M Kawamura H Takiyama I Koeda K Takagane A Pharmacokinetics of cisplatin in combined cisplatin and 5-fluorouracil therapy: a comparative study of three different schedules of cisplatin administration Jpn J Clin Oncol. 1998 28 168 75 10.1093/jjco/28.3.168 9614438 \n16. Yamada Y Ikuta Y Nosaka K Miyanari N Hayashi N Mitsuya H Successful treatment of Cisplatin overdose with plasma exchange Case Rep Med. 2010 2010 802312 20300587 \n17. Chu G Mantin R Shen YM Baskett G Sussman H Massive cisplatin overdose by accidental substitution for carboplatin Toxic Manag Cancer. 1993 72 3707 14 \n18. Schellens JH Ma J Planting AS van der Burg ME van Meerten E de Boer-Dennert M Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours Br J Cancer. 1996 73 1569 75 10.1038/bjc.1996.296 8664132 \n19. Janus N Thariat J Boulanger H Deray G Launay-Vacher V Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients Ann Oncol. 2010 21 1395 403 10.1093/annonc/mdp598 20118214\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "11(1)", "journal": "Journal of medical case reports", "keywords": "Cisplatin; Hemodialysis; Mediastinal yolk sac tumor; Pharmacokinetics; Renal insufficiency", "medline_ta": "J Med Case Rep", "mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018240:Endodermal Sinus Tumor; D005047:Etoposide; D006801:Humans; D008297:Male; D008479:Mediastinal Neoplasms; D008482:Mediastinum; D006435:Renal Dialysis; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101293382", "other_id": null, "pages": "43", "pmc": null, "pmid": "28202048", "pubdate": "2017-02-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9614438;9053482;17471115;17914077;2178277;10408483;16255135;66973;11919246;15170366;20933444;17401020;8664132;9443627;8252487;20300587;23422328;15319245;20118214", "title": "Chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report.", "title_normalized": "chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis a case report" }

[ { "companynumb": "JP-ACCORD-048843", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "074513", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSES ESCALATED FROM THE THIRD?TO THE FIFTH CYCLES: ETOPOSIDE TO 75MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "42.6", "reaction": [ { "reactionmeddrapt": "Appendicitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIRAKAWA H, NAKASHIMA C, NAKAMURA T, MASUDA M, FUNAKOSHI T, NAKAGAWA S, ET AL. CHEMOTHERAPY FOR PRIMARY MEDIASTINAL YOLK SAC TUMOR IN A PATIENT UNDERGOING CHRONIC HEMODIALYSIS: A CASE REPORT. J MED CASE REP. 2017 FEB 16;11(1):43.", "literaturereference_normalized": "chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170306", "receivedate": "20170306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13296968, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "At the extreme spectrum of consciousness during sleep, some patients with rare hypersomnias reported experiencing a specific night 'blackout' when sleeping, i.e., an absence of experiences or recall of them from sleep onset to offset. Thus, we explored through questionnaires the conscious experiences (dreaming experience, mind, self) during the night in 133 patients with idiopathic hypersomnia, 108 patients with narcolepsy, and 128 healthy controls. The night blackout was more frequent in idiopathic hypersomnia than in narcolepsy and control groups. Patients with idiopathic hypersomnia and frequent night amnesia had lower dream recall frequencies, and felt more often sleep as deep and mind as blank during the night. They had a higher proportion of slow wave sleep on their (retrospectively collected) sleep recordings than those without night blackout. This night blackout provides a new model for studying loss of consciousness during sleep, here as a contentless, selfless and timeless feeling upon awakening.", "affiliations": "Sorbonne University, Paris, France; Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France.;Sorbonne University, Paris, France.;Sorbonne University, Paris, France.;Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; National Reference Center on Narcolepsy and Rare Hypersomnias, France.;Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; National Reference Center on Narcolepsy and Rare Hypersomnias, France.;Sorbonne University, Paris, France; Paris Brain Institute (IHU@ICM; Inserm UMR_S 975; CNRS UMR 7225), Paris, France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; National Reference Center on Narcolepsy and Rare Hypersomnias, France. Electronic address: [email protected].", "authors": "Chabani|Emma|E|;Vionnet|Marie Charlotte|MC|;Beauté|Romy|R|;Leu-Semenescu|Smaranda|S|;Dodet|Pauline|P|;Arnulf|Isabelle|I|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.concog.2020.102931", "fulltext": null, "fulltext_license": null, "issn_linking": "1053-8100", "issue": "81()", "journal": "Consciousness and cognition", "keywords": "Amnesia; Blackout; Consciousness; Hypersomnia; Narcolepsy; Non-dreamer; Self", "medline_ta": "Conscious Cogn", "mesh_terms": "D000328:Adult; D000647:Amnesia; D003243:Consciousness; D004325:Dreams; D004532:Ego; D005260:Female; D006801:Humans; D020177:Idiopathic Hypersomnia; D008297:Male; D009290:Narcolepsy; D000077310:Sleep, Slow-Wave; D055815:Young Adult", "nlm_unique_id": "9303140", "other_id": null, "pages": "102931", "pmc": null, "pmid": "32339976", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Blackout of my nights: Contentless, timeless and selfless report from the night in patients with central hypersomnias.", "title_normalized": "blackout of my nights contentless timeless and selfless report from the night in patients with central hypersomnias" }

[ { "companynumb": "FR-JAZZ-2020-FR-007133", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SODIUM OXYBATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NARCOLEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XYREM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHABANI E, VIONNET MC, BEAUTE R, LEU?SEMENESCU S, DODET P, ARNULF I.. BLACKOUT OF MY NIGHTS: CONTENTLESS, TIMELESS AND SELFLESS REPORT FROM THE NIGHT IN PATIENTS WITH CENTRAL HYPERSOMNIAS. CONSCIOUSNESS AND COGNITION. 2020?81", "literaturereference_normalized": "blackout of my nights contentless timeless and selfless report from the night in patients with central hypersomnias", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200820", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18177987, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "FR-JAZZ-2020-FR-007111", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SODIUM OXYBATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021196", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XYREM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CHABANI E, VIONNET MC, BEAUTE R, LEU?SEMENESCU S, DODET P, ARNULF I.. BLACKOUT OF MY NIGHTS: CONTENTLESS, TIMELESS AND SELFLESS REPORT FROM THE NIGHT IN PATIENTS WITH CENTRAL HYPERSOMNIAS.. CONSCIOUSNESS AND COGNITION. 2020?81", "literaturereference_normalized": "blackout of my nights contentless timeless and selfless report from the night in patients with central hypersomnias", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200820", "receivedate": "20200820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18177756, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]

{ "abstract": "Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS.\n\n\n\nA 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective.\n\n\n\nThis case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.", "affiliations": "Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.;Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.;Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.;Department of Diabetes & Endocrinology, St Vincent's Hospital, Melbourne, Australia.", "authors": "Calder|Genevieve L|GL|;Ward|Glenn M|GM|;Sachithanandan|Nirupa|N|;MacIsaac|Richard J|RJ|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel", "country": "United States", "delete": false, "doi": "10.1210/clinem/dgz301", "fulltext": null, "fulltext_license": null, "issn_linking": "0021-972X", "issue": "105(4)", "journal": "The Journal of clinical endocrinology and metabolism", "keywords": "clopidogrel; hypoglycemia; insulin autoimmune syndrome", "medline_ta": "J Clin Endocrinol Metab", "mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D000077144:Clopidogrel; D006801:Humans; D007003:Hypoglycemia; D008297:Male; D017202:Myocardial Ischemia; D010975:Platelet Aggregation Inhibitors; D011379:Prognosis; D013577:Syndrome", "nlm_unique_id": "0375362", "other_id": null, "pages": null, "pmc": null, "pmid": "32182368", "pubdate": "2020-04-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Insulin Autoimmune Syndrome: A Case of Clopidogrel-induced Autoimmune Hypoglycemia.", "title_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia" }

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INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL-INDUCED AUTOIMMUNE HYPOGLYCEMIA. 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INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL-INDUCED AUTOIMMUNE HYPOGLYCEMIA. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL BISULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN [ACETYLSALICYLIC ACID]" } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anti-insulin antibody increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperplasia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insulin C-peptide increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insulin autoimmune syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood proinsulin increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood insulin increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CALDER GL, WARD GM, SACHITHANANDAN N, MACISAAC RJ.. INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL-INDUCED AUTOIMMUNE HYPOGLYCEMIA. THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. 2020?10:1?4", "literaturereference_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20200411", "receivedate": "20200408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17645340, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-257121", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, 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INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL?INDUCED AUTOIMMUNE HYPOGLYCEMIA. 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"drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXTROSE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Insulin autoimmune syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperinsulinaemic hypoglycaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CALDER GL, WAR GM, SACHITHANANDAN N, MACISAA RJ. INSULIN AUTOIMMUNE SYNDROME: A CASE OF CLOPIDOGREL?INDUCED AUTOIMMUNE HYPOGLYCEMIA. J?CLIN?ENDOCRINOL?METAB 2020?105(4):996?999.", "literaturereference_normalized": "insulin autoimmune syndrome a case of clopidogrel induced autoimmune hypoglycemia", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18145793, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]

{ "abstract": "Purulent pericarditis is a rare clinical entity in the modern antibiotic era. The most common portal of entry is thought to be direct extension from a primary lung source and is usually caused by Staphylococcus aureus, Streptococcus pneumoniae or Haemophilus influenzae We report the case of a man aged 69 years who presented with purulent pericarditis due to Enterococcus faecalis likely caused by haematogenous spread from a urinary tract source. Urgent pericardiocentesis was vital and restored his haemodynamic stability. He was treated for a total duration of 4 weeks with susceptible antibiotics. Echocardiography 3 weeks later showed persistent resolution of the pericardial effusion. This case shows that prompt diagnosis and drainage of the pericardial effusion are vital to achieve a positive outcome in purulent pericarditis. To the best of our knowledge, this is the first reported case of purulent pericarditis caused by E. faecalis from a urinary tract source.", "affiliations": "Department of Internal Medicine, Kansas University School of Medicine-Wichita, Wichita, Kansas, USA.;Department of Internal Medicine, Kansas University School of Medicine-Wichita, Wichita, Kansas, USA.;Department of Pulmonary and Critical Care Medicine, Kansas University School of Medicine-Wichita, Wichita, Kansas, USA.", "authors": "Nehme|Fredy|F|http://orcid.org/0000-0001-6433-178X;Gitau|Jane|J|;Liu|Jing|J|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-219498", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D013293:Enterococcus faecalis; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D020519:Pericardiocentesis; D010493:Pericarditis; D014552:Urinary Tract Infections", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28298381", "pubdate": "2017-03-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10433600;10967149;1138554;15001332;17670671;19352300;8227835;930941", "title": "Purulent pericarditis as a complication of bacteraemic Enterococcus faecalis urinary tract infection.", "title_normalized": "purulent pericarditis as a complication of bacteraemic enterococcus faecalis urinary tract infection" }

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SODIUM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPICILLIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ENTEROCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NEHME F, GITAU J, LIU J. PURULENT PERICARDITIS AS A COMPLICATION OF BACTERAEMIC ENTEROCOCCUS FAECALIS URINARY TRACT INFECTION. BMJ CASE REPORTS. 2017; ARTICLE NUMBER 219498.", "literaturereference_normalized": "purulent pericarditis as a complication of bacteraemic enterococcus faecalis urinary tract infection", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170616", "receivedate": "20170616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13658861, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "Bupropion inhibits the uptake of dopamine and norepinephrine. Clinical effects in overdose include seizure, status epilepticus, tachycardia, arrhythmias, and cardiogenic shock. We report two cases of severe bupropion toxicity resulting in refractory cardiogenic shock, cardiac arrest, and repeated seizures treated successfully. Patients with cardiovascular failure related to poisoning may particularly benefit from extracorporeal membrane oxygenation (ECMO). These are the first cases of bupropion toxicity treated with veno-arterial EMCO (VA-ECMO) in which bupropion toxicity is supported by confirmatory testing. Both cases demonstrate the effectiveness of VA-ECMO in poisoned patients with severe cardiogenic shock or cardiopulmonary failure.", "affiliations": "Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA. [email protected].;Department of Medical Toxicology, Banner University Medical Center Phoenix, 925 E. McDowell Road, 2nd Floor Medical Toxicology, Phoenix, AZ, 85006, USA.;Department of Medicine, Section of Critical Care, Banner University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medicine, Section of Critical Care, Banner University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medical Toxicology, Banner University Medical Center Phoenix, 925 E. McDowell Road, 2nd Floor Medical Toxicology, Phoenix, AZ, 85006, USA.", "authors": "Heise|C William|CW|;Skolnik|Aaron B|AB|;Raschke|Robert A|RA|;Owen-Reece|Huw|H|;Graeme|Kimberlie A|KA|", "chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion", "country": "United States", "delete": false, "doi": "10.1007/s13181-016-0539-7", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "12(3)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": "Bupropion; Cardiogenic shock; ECMO; Extracorporeal membrane oxygenation; Overdose; Status epilepticus", "medline_ta": "J Med Toxicol", "mesh_terms": "D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation; D001130:Arizona; D016642:Bupropion; D003131:Combined Modality Therapy; D003865:Depressive Disorder, Major; D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D012131:Respiratory Insufficiency; D012720:Severity of Illness Index; D012770:Shock, Cardiogenic; D013226:Status Epilepticus; D013406:Suicide, Attempted; D062606:Tertiary Care Centers; D016896:Treatment Outcome", "nlm_unique_id": "101284598", "other_id": null, "pages": "301-4", "pmc": null, "pmid": "26856351", "pubdate": "2016-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19822628;16027765;23238774;18062140;8305956;22469751;12831424;22615675;10332532;26624241;19897080;23697460;21623902;16183450;17766009;3936237;25454073;7665537;25634667;22087681;21206256", "title": "Two Cases of Refractory Cardiogenic Shock Secondary to Bupropion Successfully Treated with Veno-Arterial Extracorporeal Membrane Oxygenation.", "title_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation" }

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TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL. 2016;12:301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171003", "receivedate": "20171003", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14032367, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "PHHY2016US069164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, 60 TABLETS OF 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. JOURNAL OF MEDICAL TOXICOLOGY. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160519", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12385217, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-APOTEX-2016AP008517", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "076143", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60 TABLETS OF 150MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION.. J-MED-TOXICOL. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160530", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383847, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2016PRN00044", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60-150 MG TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12192948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-BAUSCH-BL-2016-004532", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WILLIAM H, SKOLNIK A, OWEN-REECE H, RASCHKE R, GRAEME K. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL. 2016 FEB 08?.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160302", "receivedate": "20160302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12138038, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-IMPAX LABORATORIES, INC-2016-IPXL-00430", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075914", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": "60 TABS OF 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE EXTENDED-RELEASE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, REECE HO, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL. 2016;1-4", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160425", "receivedate": "20160425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12302248, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-EDGEMONT-2016EDG00008", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50-90 TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160321", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12195896, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-CIPLA LTD.-2016US23956", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENOBARBITAL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG, LOADING DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, LOADING DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK, GREATER THAN 50 AS MANY AS 90", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL.. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13087656, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2016PRN00043", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202304", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50 TO 90 150-MG TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160318", "receivedate": "20160318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12192956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-MYLANLABS-2016M1020375", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "GREATER THAN 50, AND PERHAPS AS MANY AS 90, BUPROPION 150MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;:.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160518", "receivedate": "20160518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383509, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-EDGEMONT-2016EDG00009", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60-150 MG TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160321", "receivedate": "20160321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12195902, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "US-HERITAGE PHARMACEUTICALS-2016HTG00247", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "206975", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "9000 MG, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016;12(3):301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161010", "receivedate": "20161010", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12834202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170207" }, { "companynumb": "US-ZYDUS-011147", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201567", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "INGESTING 60 TABS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Pupil fixed" }, { "drugrecuraction": "Cardiogenic shock" }, { "drugrecuraction": "Status epilepticus" }, { "drugrecuraction": "Mydriasis" }, { "drugrecuraction": "Bradycardia" }, { "drugrecuraction": "Cardiac arrest" }, { "drugrecuraction": "Leukocytosis" }, { "drugrecuraction": "Cardiomyopathy" }, { "drugrecuraction": "Overdose" }, { "drugrecuraction": "Electrocardiogram QRS complex prolonged" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION/BUPROPION HYDROCHLORIDE" } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160524", "receivedate": "20160524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12396722, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "PHHY2016US066342", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "150 MG, 90 TABLETS.", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. JOURNAL OF MEDICAL TOXICOLOGY. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160520", "receivedate": "20160520", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12388942, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-MYLANLABS-2016M1020376", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075491", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "60 TABLETS OF 150MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;:.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160518", "receivedate": "20160518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383510, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-APOTEX-2016AP008514", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "076143", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "GREATER THAN 50, AND PERHAPS AS MANY AS 90", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION.. J-MED-TOXICOL. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160527", "receivedate": "20160519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12383795, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-ZYDUS-011140", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201567", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": [ { "drugrecuraction": "Status epilepticus" }, { "drugrecuraction": "Leukocytosis" }, { "drugrecuraction": "Mydriasis" }, { "drugrecuraction": "Pulmonary oedema" }, { "drugrecuraction": "Cardiogenic shock" }, { "drugrecuraction": "Pupil fixed" }, { "drugrecuraction": "Pulmonary haemorrhage" }, { "drugrecuraction": "Pneumonia aspiration" }, { "drugrecuraction": "Overdose" }, { "drugrecuraction": "Cardiomyopathy acute" }, { "drugrecuraction": "Cardiac arrest" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION/BUPROPION HYDROCHLORIDE" } ], "patientagegroup": "4", "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinus tachycardia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Creatinine urine abnormal", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urine output decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J-MED-TOXICOL 2016;.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160524", "receivedate": "20160524", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12396725, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "US-CIPLA LTD.-2016US23955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA.. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. 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TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J. MED. TOXICOL. 2016", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160425", "receivedate": "20160425", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12300941, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-116795", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "78866", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50, AND PERHAPS AS MANY AS 90, TABLET", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Cardiomyopathy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pupil fixed", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL. 2016;12:301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171003", "receivedate": "20171003", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14032371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "US-BAUSCH-BL-2016-004530", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021515", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mydriasis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE C, SKOLNIK A, RASCHKE R, OWEN-REECE H, GRAEME K. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J.MED.TOXICOL.. 2016 FEB 08?.", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160302", "receivedate": "20160302", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12138143, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-HERITAGE PHARMACEUTICALS-2016HTG00246", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPROPION HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "206975", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "50-90 TABLETS, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPROPION HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiomyopathy acute", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HEISE CW, SKOLNIK AB, RASCHKE RA, OWEN-REECE H, GRAEME KA. TWO CASES OF REFRACTORY CARDIOGENIC SHOCK SECONDARY TO BUPROPION SUCCESSFULLY TREATED WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION. J MED TOXICOL (DOI: 10.1007/S13181-016-0539-7). 2016;12(3):301-304", "literaturereference_normalized": "two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno arterial extracorporeal membrane oxygenation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161010", "receivedate": "20161010", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12834203, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "To describe the presentation and management of atypical subretinal lesions following initiation of antitubercular therapy for a tubercular choroidal granuloma.\nAn 18-year-old female was diagnosed with choroidal granuloma and shallow exudative retinal detachment in the left eye. Biopsy from a cervical lymph node was positive for tuberculosis. She was treated with antitubercular therapy (ATT) and oral steroids. After one week of therapy exudative detachment increased markedly and discrete yellowish-white subretinal lesions appeared first in the inferior periphery, then temporally and later involved the macula leading to a drop in visual acuity. A diagnosis of paradoxical worsening was considered and she was managed with a higher dose of oral corticosteroids, intravitreal methotrexate and intravitreal ranibizumab. The granuloma healed and the subretinal lesions as well as exudative detachment gradually resolved with improvement in visual acuity.\nSubretinal yellow-white lesions may develop as a paradoxical response to ATT.", "affiliations": "Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.", "authors": "Arora|Atul|A|https://orcid.org/0000-0002-2192-8479;Katoch|Deeksha|D|https://orcid.org/0000-0003-3646-5523;Jain|Sahil|S|;Singh|Simar Rajan|SR|https://orcid.org/0000-0003-0207-1913;Gupta|Vishali|V|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/09273948.2020.1780272", "fulltext": null, "fulltext_license": null, "issn_linking": "0927-3948", "issue": null, "journal": "Ocular immunology and inflammation", "keywords": "ATT; Ocular tuberculosis; SRHM; anti tubercular therapy; choroidal granuloma; paradoxical worsening; subretinal deposits", "medline_ta": "Ocul Immunol Inflamm", "mesh_terms": null, "nlm_unique_id": "9312169", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "32783681", "pubdate": "2020-08-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Yellow Subretinal Lesions following Initiation of Antituberculosis Therapy in A Tubercular Choroidal Granuloma: A Sign of Paradoxical Worsening?", "title_normalized": "yellow subretinal lesions following initiation of antituberculosis therapy in a tubercular choroidal granuloma a sign of paradoxical worsening" }

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null, "drugdosageform": null, "drugdosagetext": "300 MG, DURATION OF 9 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "(0.05 ML OF 10 MG/ML)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "0.05", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "UNK, 400 MICROGRAM /0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Tuberculosis of eye", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Arora A, Katoch D, Jain S, Singh SR, Gupta V. Yellow Subretinal Lesions following Initiation of Antituberculosis Therapy in A Tubercular Choroidal Granuloma: A Sign of Paradoxical Worsening?. Ocular immunology and inflammation. 2022;30(1):29-33", "literaturereference_normalized": "yellow subretinal lesions following initiation of antituberculosis therapy in a tubercular choroidal granuloma a sign of paradoxical worsening", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20956167, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "IN-SA-2020SA225862", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PYRAZINAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PYRAZINAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBRETINAL HYPERREFLECTIVE EXUDATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ETHAMBUTOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "1000 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETHAMBUTOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "031", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.05 ML OF 10 MG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "300 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBERCULOSIS OF EYE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "031", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.05 ML OF 10 MG/ML (SECOND DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBRETINAL HYPERREFLECTIVE EXUDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subretinal hyperreflective exudation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paradoxical drug reaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retinal detachment", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARORA A, KATOCH D, JAIN S, SINGH SR, GUPTA V. YELLOW SUBRETINAL LESIONS FOLLOWING INITIATION OF ANTITUBERCULOSIS THERAPY IN A TUBERCULAR CHOROIDAL GRANULOMA: A SIGN OF PARADOXICAL WORSENING. OCUL IMMUNOL INFLAMM.. 2020?UNK:UNK", "literaturereference_normalized": "yellow subretinal lesions following initiation of antituberculosis therapy in a tubercular choroidal granuloma a sign of paradoxical worsening", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200902", "receivedate": "20200902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18220843, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is known to be a rare and aggressive form of lymphoma that relapses quickly after both conventional chemotherapy and more targeted therapy. Lenalidomide is an immunomodulator that has shown safety and efficacy in multiple myeloma and is also approved for use in several types of lymphoma. In the case described here, the patient had a significant partial response to lenalidomide, which has not previously been described in this type of lymphoma. Given how aggressive and difficult to treat ALK+ LBCL is, further research is warranted to more completely elucidate the mechanism of action of lenalidomide in ALK+ LBCL and its role in treatment.", "affiliations": "Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.;Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.;Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA [email protected].", "authors": "Bhaskar|Shakthi|S|;Abro|Brooj|B|;Fraum|Tyler J|TJ|;Mehta-Shah|Neha|N|", "chemical_list": "D007155:Immunologic Factors; D000077548:Anaplastic Lymphoma Kinase; D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-235578", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(8)", "journal": "BMJ case reports", "keywords": "cancer intervention; therapeutic indications", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D000077269:Lenalidomide; D017728:Lymphoma, Large-Cell, Anaplastic; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32843459", "pubdate": "2020-08-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase-positive large B-cell lymphoma.", "title_normalized": "lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase positive large b cell lymphoma" }

[ { "companynumb": "US-CELGENEUS-USA-20200900325", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": "15 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": "20 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" } ], "patientagegroup": null, "patientonsetage": "84", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spinal fracture", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Performance status decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dementia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHASKAR S. LENALIDOMIDE DEMONSTRATES CLINICAL ACTIVITY IN ANAPLASTIC LYMPHOMA KINASE?POSITIVE LARGE B?CELL LYMPHOMA. BMJ CASE REPORTS. 2020 AUG 25?.", "literaturereference_normalized": "lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase positive large b cell lymphoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200909", "receivedate": "20200909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18245746, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Platinum-based chemotherapeutic agents are commonly used in the treatment of several cancers. While effective, they are often discontinued due to toxicities and hypersensitivity reactions (HSRs) that occur more frequently with repeated exposure. Following discontinuation of one agent, therapy may be continued with a second platinum salt, though the cross-reactivity between agents in this class is not well understood. This is particularly true for alternative routes of administration such as hyperthermic intraperitoneal chemotherapy (HIPEC). In this case report, we describe the use of cisplatin during HIPEC in a patient who previously experienced an HSR to systemic oxaliplatin. The patient tolerated HIPEC including 200 mg cisplatin for 1 hour without any adverse effects and did not require a desensitization protocol prior to therapy. This case suggests that HIPEC with platinum-based agents can be performed in patients with prior HSRs to systemic therapy, though further studies are needed to understand safety parameters, the cross-reactivity between agents and the necessity of skin testing or desensitization protocols.", "affiliations": "Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.;Department of Pharmacy, University of Chicago Medical Center, Chicago, IL, USA.;Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.;Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.", "authors": "Morgan|Ryan|R|https://orcid.org/0000-0002-4201-166X;Parsad|Sandeep|S|https://orcid.org/0000-0002-7256-7212;Turaga|Kiran K|KK|https://orcid.org/0000-0001-8541-586X;Eng|Oliver S|OS|https://orcid.org/0000-0003-0226-5005", "chemical_list": "D000077150:Oxaliplatin; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1111/bcpt.13464", "fulltext": null, "fulltext_license": null, "issn_linking": "1742-7835", "issue": "127(6)", "journal": "Basic & clinical pharmacology & toxicology", "keywords": "HIPEC; cisplatin; hypersensitivity; oxaliplatin; platinum salt", "medline_ta": "Basic Clin Pharmacol Toxicol", "mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018450:Disease Progression; D004342:Drug Hypersensitivity; D006801:Humans; D000084262:Hyperthermic Intraperitoneal Chemotherapy; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D000077150:Oxaliplatin; D013274:Stomach Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "101208422", "other_id": null, "pages": "551-553", "pmc": null, "pmid": "32623784", "pubdate": "2020-12", "publication_types": "D002363:Case Reports", "references": null, "title": "HIPEC with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin.", "title_normalized": "hipec with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin" }

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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": "5", "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chest discomfort", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lip swelling", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORGAN R, PARSAD S, TURAGA KK, ENG OS. HIPEC WITH CISPLATIN IN A PATIENT WITH A PRIOR HYPERSENSITIVITY REACTION TO SYSTEMIC OXALIPLATIN. BASIC?CLIN?PHARMACOL?TOXICOL 2020?:NO PAGINATION.", "literaturereference_normalized": "hipec with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200831", "receivedate": "20200826", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18198949, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-CIPLA LTD.-2020US05570", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, 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"reactionmeddrapt": "Gastrointestinal toxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MORGAN R, PARSAD S, TURAGA KK, ENG OS.. HIPEC WITH CISPLATIN IN A PATIENT WITH A PRIOR HYPERSENSITIVITY REACTION TO SYSTEMIC OXALIPLATIN. BASIC AND CLINICAL PHARMACOLOGY AND TOXICOLOGY. 2020?00:1 TO 3", "literaturereference_normalized": "hipec with cisplatin in a patient with a prior hypersensitivity reaction to systemic oxaliplatin", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200814", "receivedate": "20200814", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18147943, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "BACKGROUND Serotonin syndrome is a common yet potentially life-threatening condition caused by increased serotonergic activity, usually from serotonergic pharmaceutical agents. Primary features of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. However, the presentation of serotonin syndrome is often quite variable, leading to its under-diagnosis. CASE REPORT A 50-year-old female with chronic kidney disease on peritoneal dialysis presented to the Emergency Department with severe, diffuse body pain. Over the course of her hospital stay, she developed severe nausea, vomiting, and diarrhea followed by hyperreflexia and inducible clonus. Laboratory studies were remarkable for elevated liver transaminases. Review of her medications revealed several serotonergic agents, including duloxetine, tramadol, and ondansetron. Given her symptoms and the multiple serotonergic agents she was taking, she was diagnosed with serotonin syndrome. Discontinuation of the serotonergic agents led to resolution of her symptoms over the course of 4 days. CONCLUSIONS Our patient's initial presentation of diffuse body pain highlights the variable presentation of serotonin syndrome. Our case also demonstrates the importance of recognizing serotonin syndrome, as the supportive ondansetron we gave to alleviate her nausea and vomiting likely exacerbated her serotonin syndrome.", "affiliations": "University of Florida College of Medicine, Gainesville, FL, USA.;University of Florida College of Medicine, Gainesville, FL, USA.;Department of Medicine, University of Florida, Gainesville, FL, USA.;Department of Medicine, University of Florida, Gainesville, FL, USA.", "authors": "Guo|Michael H|MH|;Monir|Reesa L|RL|;Wright|Ashleigh|A|;Holland|Neal P|NP|", "chemical_list": "D017367:Serotonin Uptake Inhibitors", "country": "United States", "delete": false, "doi": "10.12659/AJCR.911204", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3031850410.12659/AJCR.911204911204ArticlesCase of Serotonin Syndrome Initially Presenting as Diffuse Body Pain Guo Michael H. ABCDEFG1Monir Reesa L. ABCDEF1Wright Ashleigh ACDE2Holland Neal P. ABCDEFG2\n1 University of Florida College of Medicine, Gainesville, FL, U.S.A.\n2 Department of Medicine, University of Florida, Gainesville, FL, U.S.AAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Neal P. Holland, e-mail: [email protected] 15 10 2018 19 1227 1231 17 5 2018 12 7 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 50\n\nFinal Diagnosis: Serotonin syndrome\n\nSymptoms: Pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: General and Internal Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nSerotonin syndrome is a common yet potentially life-threatening condition caused by increased serotonergic activity, usually from serotonergic pharmaceutical agents. Primary features of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. However, the presentation of serotonin syndrome is often quite variable, leading to its under-diagnosis.\n\nCase Report:\nA 50-year-old female with chronic kidney disease on peritoneal dialysis presented to the Emergency Department with severe, diffuse body pain. Over the course of her hospital stay, she developed severe nausea, vomiting, and diarrhea followed by hyperreflexia and inducible clonus. Laboratory studies were remarkable for elevated liver transaminases. Review of her medications revealed several serotonergic agents, including duloxetine, tramadol, and ondansetron. Given her symptoms and the multiple serotonergic agents she was taking, she was diagnosed with serotonin syndrome. Discontinuation of the serotonergic agents led to resolution of her symptoms over the course of 4 days.\n\nConclusions:\nOur patient’s initial presentation of diffuse body pain highlights the variable presentation of serotonin syndrome. Our case also demonstrates the importance of recognizing serotonin syndrome, as the supportive ondansetron we gave to alleviate her nausea and vomiting likely exacerbated her serotonin syndrome.\n\nMeSH Keywords:\nAbnormalities, Drug-InducedAntidepressive AgentsSerotonin Syndrome\n==== Body\nBackground\nSerotonin syndrome, or serotonin toxicity, is a constellation of symptoms that result from increased serotonergic activity. The syndrome is usually caused by increased serotonin levels as a result of medications that have serotonergic activity. Although serotonin syndrome is classically caused by selective serotonin reuptake inhibitors (SSRIs), other pharmaceutical agents have also been implicated. These including antipsychotics, narcotics, dietary supplements, anti-epileptics, and antibiotics, among many others [1]. The syndrome is quite common, although reliable estimates of its prevalence have been hampered by challenges with recognition of the syndrome owing to its variable presentation. However, a post-marketing surveillance study of the SSRI nefazodone identified an incidence of 0.4 cases per 1000 patient-months [2]. In addition, a study revealed that 14–16% of cases of overdose of SSRIs develop symptoms of serotonin syndrome [3].\n\nSerotonin syndrome is the result of increased serotonin in the central nervous system (CNS) and peripheral nervous system [3]. It is believed that the serotonin receptor 5-HT2A is primarily responsible for these effects, although other neurotransmitter receptors have also been implicated [4,5]. In the CNS, serotonin is normally produced from the median raphe nucleus and has a wide range of effects on behavior, mood appetite, autonomic function, thermoregulation, and nociception, amongst others. In the periphery, serotonin acts to modulate gastrointestinal motility and vascular tone. The clinical manifestations of serotonin syndrome are a reflection of the effects of excessive serotonin on these physiologic systems.\n\nThe classic clinical triad of serotonin syndrome is comprised of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities (Table 1). However, the clinical presentation of serotonin syndrome is quite variable and non-specific [6], often making the diagnosis quite challenging. Furthermore, no single laboratory test, including serum serotonin levels, can reliably confirm the diagnosis, and there are no pathognomonic clinical findings [7]. Currently, the Hunter Criteria is the best diagnostic criteria (Table 1), and has a reported sensitivity of 84% and specificity of 97% [7]. Timely diagnosis is imperative, as serotonin syndrome can be life-threatening given the autonomic instability. Life-threatening and related complications of the condition include severe hypertension and tachycardia that lead to shock, hyperthermia, rhabdomyolysis, renal failure, and disseminated intravascular coagulation, among others [1]. The cornerstone of treatment is discontinuation of all serotonergic agents and supportive measures [1], as well as possible administration of anti-serotonergic agents such as cyproheptadine in more severe cases [8].\n\nCase Report\nA 50-year-old female with medical history notable for stage 5 chronic kidney disease on nightly home peritoneal dialysis, type II diabetes mellitus, peripheral neuropathy, gastroesophageal reflux disease, hypertension, and unspecified chronic pain presented to the Emergency Department (ED) with a 1-day history of worsened nausea and severe diffuse body pain, most notably of her abdomen. Her pain began the evening prior to admission during a home peritoneal dialysis treatment, which she stopped promptly due to the development of her severe pain.\n\nOn review of her history, she had experienced similar symptoms approximately 1 month ago, also during a home perito-neal dialysis session. With the prior episode, the pain subsided when she stopped her dialysis session. It was later determined by her nephrologist that this pain was caused by gas introduced during dialysis.\n\nOn initial physical examination, she appeared anxious and acutely in distress from her pain. Vital signs revealed that she was afebrile and with blood pressure of 148/82 mmHg, heart rate of 109 beats per minute and respiratory rate of 18 breaths per minute. She complained of pain on light palpation to any portion of her body, including her entire abdomen. Her cardiac and pulmonary examinations were unremarkable. Her liver span and spleen size could not be determined as the patient was unable to tolerate examination. No ascites or edema was noted. She was able to move all extremities spontaneously, and no focal neurological deficits were observed. She did display bilateral asterixis. Her deep tendon reflexes were normal on initial exam, and her tone was judged to be normal.\n\nIn the ED, initial laboratory investigations revealed elevated blood urea nitrogen (BUN) and creatinine levels, consistent with her chronic kidney disease and not changed significantly from baseline (Table 2). She had a normocytic, normochromic anemia, which was unchanged from her baseline, but her white blood cell count and differential was within normal limits. Liver enzymes were notable for increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase, but her bilirubin was within normal limits.\n\nHepatitis A, B, and C serologies were all negative. Serum lipase was not elevated. Peritoneal fluid analysis was also performed. Peritoneal fluid was cloudy and showed elevated white blood cells (WBCs) (4% neutrophils), but the gram stain of her peritoneal fluid did not show any organisms (Table 3).\n\nComputed tomography with IV contrast of the abdomen was performed. It was remarkable for wedge-shaped areas of hypodensity in the spleen that were read as possibly representing infarction. A right upper quadrant ultrasound was unremarkable, with no abnormal findings in the liver, gallbladder, pancreas, or biliary tree.\n\nShe was admitted to the hospital with concern that her pain was again related to her peritoneal dialysis catheter or her dialysis treatment. Over the first 3 days of her hospitalization, her pain worsened. In addition, she developed worsening nausea, severe retching, non-bloody diarrhea, and recurrent non-bloody, non-bilious vomiting. She was given ondansetron for symptomatic treatment of her nausea without relief. She was switched to promethazine, but her symptoms continued to worsen. She also had episodic hypertension, with systolic blood pressure as high as 234 mmHg. She continued to display asterixis, and on day 3 of hospitalization, she was found to have inducible clonus and new patellar hyperreflexia bilaterally.\n\nGiven the negative workup, her medication history was reviewed carefully in search for an underlying cause for her symptoms. On further review, it was noted that she had been taking multiple pharmaceutical agents with serotonergic properties. She was prescribed duloxetine (30 mg oral twice a day) for her peripheral neuropathy and had been using tramadol (50 mg oral) on an as needed basis for pain as well. She also was taking promethazine (12.5–25 mg oral) at home as needed for mild nausea. During her hospital stay, she was given a total of 16 mg in doses of 4 mg of ondansetron for symptomatic treatment of her nausea and vomiting, which was switched to promethazine when ondansetron was ineffective and received one 25 mg dose of intravenous promethazine. Duloxetine, tramadol, and ondansetron all have serotonergic properties and have been known to cause or contribute to serotonin syndrome [1]. Given her overall presentation and when considering her mediation use, she was diagnosed with serotonin syndrome.\n\nFollowing our diagnosis of serotonin syndrome, we discontinued all of her serotonergic medications, including duloxetine, tramadol, and ondansetron. We also discontinued her promethazine, as promethazine is associated with neuroleptic malignant syndrome, an important differential diagnosis whose features can mimic serotonin syndrome (see Discussion). As she did not exhibit life-threatening autonomic instability, more aggressive measures such as cyproheptadine were not warranted in her case. She was closely observed, with daily laboratory investigations and close tracking of her vital signs. She started to improve symptomatically within 1 day of discontinuation of her serotonergic agents. By day 3 (hospital day 6) following discontinuation of her serotonergic agents, her diffuse pain, clonus, and tremor had resolved. Her liver enzymes also trended down and were nearly completely normalized by day 6 of hospitalization.\n\nWith resolution of her symptoms, she was discharged after discontinuation of her serotonergic agents. She was instructed to follow up with her primary care provider to consider restarting her duloxetine for her underlying chronic pain under close monitoring.\n\nDiscussion\nThis patient initially presented with a variety of symptoms that did not fit a single unifying diagnosis. Her initial presenting symptoms of severe, diffuse, non-anatomical pain that was seemingly temporally related to her peritoneal dialysis caused us to consider primarily gastrointestinal and somatoform etiologies. However, when she developed clonus and hyperreflexia as well as numerous autonomic symptoms (nausea, vomiting, diarrhea, and episodic hypertension) during her hospital stay, we were able to recognize her constellation of symptoms as serotonin syndrome.\n\nCareful medication review did reveal several serotonergic agents the patient was taking prior to admission – duloxetine and tramadol. Furthermore, as her symptoms progressed and worsened during her stay, she was given ondansetron and promethazine at increasing dosages for symptomatic relief. Ondansetron inhibits the serotonin receptor 5-HT3, and for unclear reasons, has been associated with serotonin syndrome [9,10]. The combination of these medications allowed more classic symptoms and exam findings of serotonin syndrome (e.g., clonus and hyperreflexia) to manifest and allowed us to make the diagnosis. Our diagnosis was corroborated by the rapid resolution of symptoms following discontinuation of the serotonergic agents over the course of 4 days.\n\nA confounding aspect of this case is the temporal relationship of her symptoms to her peritoneal dialysis. In the present incident, as well as in the incident 1 month prior, she experienced severe diffuse pain following peritoneal dialysis. In the incident 1 month prior, her nephrologist had determined that gas had entered the peritoneum to trigger the pain episode. However, during this episode, no malfunction of the peritoneal dialysis catheter or the dialysis process itself could be identified. We believe that in both episodes, a possible malfunction related to her peritoneal dialysis occurred, but at this point, we do not believe that the peritoneal dialysis itself was the direct instigator of her serotonin syndrome.\n\nA diagnostic consideration in this case was neuroleptic malignant syndrome (NMS). NMS is associated with use of anti-psychotics, including promethazine, which the patient was taking prior to admission and which was additionally given to her for nausea while in the hospital [11]. NMS is classically associated with fever, muscular rigidity, and autonomic dysfunction, thus sharing many features with serotonin syndrome. However, there were several reasons why we favored serotonin syndrome over NMS. First, the patient was afebrile on admission. Second, the patient did not display frank muscle rigidity that is classic for NMS. Lastly, NMS is usually associated with abrupt escalations in the causal agent, and there was no indication that this was the case prior to her admission. Nonetheless, NMS is an important differential diagnosis in cases of serotonin syndrome. Another diagnostic consideration in this case was malignant hyperthermia, which is characterized by fever, muscular rigidity, and tachycardia [12].\n\nHowever, malignant hyperthermia is usually associated with use of depolarizing anesthetic agents (which the patient was not taking), and the patient was afebrile.\n\nIn addition, the patient had moderately elevated liver transaminases on admission (Table 2). They were noted to be down trending on follow-up labs on hospital day 2 and continued to downtrend to near normal levels after we discontinued her serotonergic agents. Prior reports have also indicated that increased liver transaminases can be seen in serotonin syndrome [1,13]. Our report provides additional evidence of elevated liver transaminases as a possible feature of serotonin syndrome.\n\nThe patient’s presenting symptom of diffuse pain is not typically associated with serotonin syndrome. However, a recent 12 patient case series identified generalized pain in 4 patients (33%) with serotonin syndrome [14]. Moreover, clonus, which is often considered as a cardinal symptom of serotonin syndrome, was only seen in 5 of the 12 patients in that study (42%). These results highlight the significant variability of serotonin syndrome and the importance for clinicians to be vigilant for this diagnosis.\n\nAn important point in this case is our initial use of ondansetron – a drug with serotonin-modifying properties – for symptomatic treatment of the patient’s nausea. Our liberal use of these medications very likely exacerbated her serotonin syndrome, worsening her nausea, vomiting, and diarrhea and allowing the clonus and hyperreflexia to manifest. Thus, it is important to recognize serotonin syndrome early, as symptomatic treatment of its symptoms may involve use of medications that will greatly worsen the condition.\n\nConclusions\nDiffuse body pain may be an initial presentation of serotonin syndrome. Medications such as ondansetron used to symptomatically treat the nausea and vomiting that may accompany serotonin syndrome can actually exacerbate the condition.\n\nTable 1. Symptoms associated with serotonin syndrome.\n\nHunter criteria symptoms of serotonin syndrome\t\n• Clonus\t\n – Spontaneous\t\n – Inducible\t\n – Ocular\t\n• Tremor\t\n• Hyperreflexia\t\n• Hypertonia\t\n• Hyperthermia\t\nOther manifestations\t\n• Altered mental status\t\n• Autonomic instability\t\n – Tachycardia\t\n – Hyperthermia\t\n – Hypertension\t\n – Vomiting\t\n• Diarrhea\t\n• Mydriasis\t\n• Diaphoresis\t\n• Pain\t\n• Flushing\t\n• Trismus\t\nTable 2. Selected laboratory measurements on admission.\n\nLab\tValue\tReference range\t\nWhite blood cell count\t7.7\t4.0–10.0 103/mL\t\nHemoglobin\t9.8\t12.0–16.0 g/dL\t\nHematocrit\t29.7\t35.9–45.0%\t\nMean corpuscular volume\t94.2\t78.0–100.0 fL\t\nPlatelet Count\t230\t150–400 103/mL\t\nAspartate aminotransferase (AST)\t572\t0–37 IU/L\t\nAlanine aminotransferase (ALT)\t391\t0–41 IU/L\t\nDirect Bilirubin\t<0.2\t0.0–0.2 mg/dL\t\nTotal Bilirubin\t0.3\t0.0–1.0 mg/dL\t\nAlkaline phosphatase\t433\t35–129 IU/L\t\nBlood urea nitrogen\t75\t6–20 mg/dL\t\nCreatinine\t10.42\t0.40–0.9 mg/dL\t\nTable 3. Peritoneal fluid analysis.\n\nLab\tValue\tReference range\t\nAppearance\tCloudy\tNA\t\nWhite blood cell count\t1410\t<5/mL\t\n Eosinophil %\t4\t0–0%\t\n Polymorphonuclear %\t4\t0–0%\t\n Monocyte/macrocyte %\t61\t0–0%\t\n Lymphocyte %\t31\t0–0%\t\nRed blood cell count\t570\t0/mL\n==== Refs\nReferences:\n1. Boyer EW Shannon M The serotonin syndrome N Engl J Med 2005 352 1112 20 15784664 \n2. Mackay FJ Dunn NR Mann RD Antidepressants and the serotonin syndrome in general practice Br J Gen Pract 1999 49 871 74 10818650 \n3. Isbister GK Bowe SJ Dawson A Whyte IM Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose J Toxicol Clin Toxicol 2004 42 277 85 15362595 \n4. Nisijima K Shioda K Yoshino T Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome Neurochem Int 2003 43 155 64 12620284 \n5. Nisijima K Yoshino T Yui K Katoh S Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome Brain Res 2001 890 23 31 11164765 \n6. Frank C Recognition and treatment of serotonin syndrome Can Fam Physician 2008 54 988 92 18625822 \n7. Dunkley EJC Isbister GK Sibbritt D The hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity QJM 2003 96 635 42 12925718 \n8. Lappin RI Auchincloss EL Treatment of the serotonin syndrome with cyproheptadine N Engl J Med 1994 331 1021 22 \n9. Turkel SB Nadala JGB Wincor MZ Possible serotonin syndrome in association with 5-HT3 antagonist agents Psychosomatics 2001 42 258 60 11351116 \n10. Gollapudy S Kumar V Dhamee MS A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion J Clin Anesth 2012 24 251 52 22537574 \n11. Berman BD Neuroleptic malignant syndrome: A review for neurohospitalists Neurohospitalist 2011 1 41 47 23983836 \n12. Glahn KPE Ellis FR Halsall PJ Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group Br J Anaesth 2010 105 417 20 20837722 \n13. Malik A Junglee N A case of the serotonin syndrome secondary to phenelzine monotherapy at therapeutic dosing Case Rep Med 2015 2015 931963 25861278 \n14. Prakash S Patel V Kakked S Mild serotonin syndrome: A report of 12 cases Ann Indian Acad Neurol 2015 18 226 30 26019424\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "19()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D059350:Chronic Pain; D005260:Female; D006801:Humans; D008875:Middle Aged; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors", "nlm_unique_id": "101489566", "other_id": null, "pages": "1227-1231", "pmc": null, "pmid": "30318504", "pubdate": "2018-10-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11164765;12925718;12620284;25861278;15362595;22537574;8084345;20837722;11351116;10818650;26019424;15784664;18625822;23983836", "title": "Case of Serotonin Syndrome Initially Presenting as Diffuse Body Pain.", "title_normalized": "case of serotonin syndrome initially presenting as diffuse body pain" }

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null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO M, MONIR R, WRIGHT, HOLLAND N. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN.. THE AMERICAN JOURNAL OF CASE REPORTS. 2018?19:1227-1231. DOI:10.12659/AJCR.911204", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190506", "receivedate": "20190107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15792767, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-ZYDUS-036677", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090404", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL OF 16MG IN DOSES OF 4MG OF ONDANSETRON", "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "040596", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5-25 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090728", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE/DULOXETINE HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL OF 16MG IN DOSES OF 4MG OF ONDANSETRON", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "040596", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "040596", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Normochromic normocytic anaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retching", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asterixis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO MH, MONIR RL, WRIGHT A, HOLLAND NP. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. AM-J-CASE-REP 2018?191227-1231.", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190511", "receivedate": "20190511", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16301468, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-QILU PHARMACEUTICAL CO.LTD.-QLU-000784-2018", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, PRN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "203711", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL OF 16 MG, IN DOSES OF 4 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5-25 MG, AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Clonus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retching", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperreflexia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asterixis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO MH MONIR RL WRIGHT A HOLLAND NP. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. AM J CASE REP.. 2018?19:1227-1231", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181105", "receivedate": "20181105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15585742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2019-US-1049602", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "76759", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED A TOTAL OF 16MG IN DOSES OF 4MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "75982", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS NEEDED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090776", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": 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CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. 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"drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUROPATHY PERIPHERAL", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DULOXETINE." } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO, M.. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. THE AMERICAN JOURNAL OF CASE REPORTS. 2018?19:1227?1231", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210728", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15598060, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-18-08121", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "083312", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING HER HOSPITAL STAY, SHE RECEIVED ONE 25 MG DOSE OF INTRAVENOUS PROMETHAZINE ; 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AS NECESSARY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076780", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": "16", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "076780", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": "16", "drugcumulativedosageunit": "003", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Serotonin syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUO M,MONIR R,WRIGHT A,HOLLAND N. CASE OF SEROTONIN SYNDROME INITIALLY PRESENTING AS DIFFUSE BODY PAIN. THE AMERICAN JOURNAL OF CASE REPORTS 2018?19:1227-1231.", "literaturereference_normalized": "case of serotonin syndrome initially presenting as diffuse body pain", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181107", "receivedate": "20181107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15595920, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "OBJECTIVE\nTo describe a paradigm of care for patients with ocular inflammatory diseases aimed at induction of durable remission.\n\n\nMETHODS\nRetrospective cohort study. The records of 399 patients with ocular inflammatory diseases treated with systemic immunomodulatory therapy (IMT) at the Massachusetts Eye Research and Surgery Institution were reviewed. Durable remission was defined as control of inflammation in the absence of systemic IMT for at least 1 year. Fifty patients met the inclusion criteria.\n\n\nRESULTS\nMean age was 46+/-22.5 years (range 18-88). All the patients had corticosteroid therapy and failed this therapy before having IMT. Fifty-two percent of the patients had used methotrexate alone or in combination with other medications. Thirty percent of the patients required at least 2 years of therapy with systemic IMT to obtain durable remission, while 44% required 2 to 5 years of therapy to achieve the same. Twenty percent continued to stay in remission, off immunomodulatory drugs, between 2 and 5 years and 18% were in remission for more than 5 years after therapy discontinuation.\n\n\nCONCLUSIONS\nIMT can be sight saving in patients. It can be tapered and discontinued successfully without the return of ocular inflammation. Durable drug-free remission is an achievable goal, and should be pursued by ocular inflammatory disease specialists.", "affiliations": "Massachusetts Eye Research and Surgery Institution, Cambridge, MA 02142, USA.", "authors": "Cervantes-Castaneda|R A|RA|;Bhat|P|P|;Fortuna|E|E|;Acevedo|S|S|;Foster|C S|CS|", "chemical_list": "D007155:Immunologic Factors; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1177/112067210901900117", "fulltext": null, "fulltext_license": null, "issn_linking": "1120-6721", "issue": "19(1)", "journal": "European journal of ophthalmology", "keywords": null, "medline_ta": "Eur J Ophthalmol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017211:Treatment Failure; D014605:Uveitis; D055815:Young Adult", "nlm_unique_id": "9110772", "other_id": null, "pages": "118-23", "pmc": null, "pmid": "19123158", "pubdate": "2009", "publication_types": "D016428:Journal Article", "references": null, "title": "Induction of durable remission in ocular inflammatory diseases.", "title_normalized": "induction of durable remission in ocular inflammatory diseases" }

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Induction of durable remission in ocular inflammatory diseases.. European Journal of Ophthalmology. 2009;19(1):118-123", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220603", "receivedate": "20220603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20909917, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220720" }, { "companynumb": "NVSC2021US179853", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EYE INFLAMMATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "EYE INFLAMMATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CERVANTES?CASTANEDA RA, BHAT P, FORTUNA E, ACEVEDO S, FOSTER S. INDUCTION OF DURABLE REMISSION IN OCULAR INFLAMMATORY DISEASES. EUROPEAN JOURNAL OF OPHTHALMOLOGY. 2009?19(1):118?23", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210811", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19687367, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-APOTEX-2021AP032195", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunomodulatory therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cervantes-Castaneda RA, Bhat P, Fortuna E, Acevedo S, Foster CS.. Induction of durable remission in ocular inflammatory diseases.. European Journal of Ophthalmology. 2009;19 (1):118-123", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220603", "receivedate": "20220603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20910016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" }, { "companynumb": "US-APOTEX-2021AP032190", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Eye inflammation", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "065040", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunomodulatory therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypercholesterolaemia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cervantes-Castaneda RA, Bhat P, Fortuna E, Acevedo S, Foster CS.. Induction of durable remission in ocular inflammatory diseases.. European Journal of Ophthalmology. 2009;19(1):118-123", "literaturereference_normalized": "induction of durable remission in ocular inflammatory diseases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220603", "receivedate": "20220603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20909580, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "BACKGROUND\nConcerns about the side effects and interactions of biologic drugs with reproduction and pregnancy have been always an issue between experts. The safety of these therapies during conception and/or pregnancy is not fully understood. The aim of this study was to assess the exposure to biologic drugs before and/or during conception/pregnancy and the risk of adverse pregnancy outcomes in women with rheumatic diseases.\n\n\nMETHODS\nWe conducted a cohort study of pregnancies reported in women with immune-mediated rheumatic diseases registered at the Rheumatic Diseases Portuguese Registry (Reuma.pt) and exposed to biologic drugs. Data concerning fetal and maternal outcomes (live birth, spontaneous abortion, neonatal and intrauterine death, intrauterine growth restriction, premature delivery, congenital malformations, neonatal lupus, voluntary or medical interruption of pregnancy, disease flares and need for treatment with other drugs) was extracted.\n\n\nRESULTS\nIn total, 69 pregnancies from 56 females were analysed, the majority with the diagnosis of spondyloarthritis or rheumatoid arthritis. In almost half of the cases (n=32, 46.4%) the biologic was stopped for pregnancy planning, in 31 cases (44.9%) it was stopped when pregnancy was diagnosed and in 6 pregnancies (8.7%) biologic therapy was maintained, at least until the 2nd trimester. There were 76.8% of live births and 22% of spontaneous abortions. Congenital anomalies were reported in 2 newborns.\n\n\nCONCLUSIONS\nIn half cases, it was decided to stop biologic therapy in the family planning period. Using biologic disease-modifying anti-rheumatic drugs before and/or during pregnancy doesn't seem to affect the overall maternal and fetal outcomes. Pregnancy planning and treatment options should be discussed and a shared decision should be established between physician and patient.", "affiliations": "Centro Hospitalar e Universitário de Coimbra.;Instituto Português de Reumatologia.;Unidade Local de Saúde do Alto Minho.;Centro Hospitalar Lisboa Ocidental.;Centro Hospitalar Tondela Viseu.;Centro Hospitalar Baixo Vouga.;Hospital Garcia da Orta.;Hospital Central do Funchal.;Centro Hospitalar e Universitário Lisboa Norte.;Centro Hospitalar Algarve.;Centro Hospitalar S.João.;Centro Hospitalar e Universitário de Coimbra.;Centro Hospitalar e Universitário de Coimbra.;Hospital Garcia da Orta.", "authors": "Brites|Luisa|L|;Madeira|Nathalie|N|;Rodrigues|Joana|J|;Marona|José|J|;Martins|Nádia|N|;Águeda|Ana|A|;Freitas|Raquel|R|;Neto|Agna|A|;Capela|Susana|S|;Sequeira|Graça|G|;Ganhão|Sara|S|;Duarte|Cátia|C|;Santiago|Mariana|M|;Santos|Maria José|MJ|", "chemical_list": "D018501:Antirheumatic Agents", "country": "Portugal", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0303-464X", "issue": "44(4)", "journal": "Acta reumatologica portuguesa", "keywords": null, "medline_ta": "Acta Reumatol Port", "mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001691:Biological Therapy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D016742:Preconception Care; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011295:Prenatal Care; D012189:Retrospective Studies; D012216:Rheumatic Diseases", "nlm_unique_id": "0431702", "other_id": null, "pages": "266-272", "pmc": null, "pmid": "32008032", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": null, "title": "Biologic therapy use and pregnancy outcomes in women with immune-mediated inflammatory rheumatic diseases.", "title_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases" }

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BIOLOGIC THERAPY USE AND PREGNANCY OUTCOMES IN WOMEN WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES. ACTA-REUMATOL-PORT 2019?44(4):266-272.", "literaturereference_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571628, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "PT-MYLANLABS-2020M1098884", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": "1", "drugadministrationroute": "064", "drugauthorizationnumb": "761154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cleft palate", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRITES L, MADEIRA N, RODRIGUES J, MARONA J, MARTINS N, AGUEDA A, ET AL. BIOLOGIC THERAPY USE AND PREGNANCY OUTCOMES IN WOMEN WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES. ACTA-REUMATOL-PORT 2019?44(4):266-272.", "literaturereference_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571549, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "PT-MYLANLABS-2020M1098901", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": "1", "drugadministrationroute": "064", "drugauthorizationnumb": "761154", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypospadias", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRITES L, MADEIRA N, RODRIGUES J, MARONA J, MARTINS N, AGUEDA A, ET AL. BIOLOGIC THERAPY USE AND PREGNANCY OUTCOMES IN WOMEN WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES. ACTA-REUMATOL-PORT 2019?44(4):266-272.", "literaturereference_normalized": "biologic therapy use and pregnancy outcomes in women with immune mediated inflammatory rheumatic diseases", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20201202", "receivedate": "20201202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18571632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]

{ "abstract": "BACKGROUND\nLacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration.\n\n\nRESULTS\nA 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship.\n\n\nCONCLUSIONS\nThis case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.", "affiliations": null, "authors": "Sunwoo|Jun-Sang|JS|;Byun|Jung-Ick|JI|;Lee|Sang Kun|SK|", "chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D015415:Biomarkers; D000078334:Lacosamide; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase", "country": "Germany", "delete": false, "doi": "10.5414/CP202282", "fulltext": null, "fulltext_license": null, "issn_linking": "0946-1965", "issue": "53(6)", "journal": "International journal of clinical pharmacology and therapeutics", "keywords": null, "medline_ta": "Int J Clin Pharmacol Ther", "mesh_terms": "D000081:Acetamides; D000410:Alanine Transaminase; D000927:Anticonvulsants; D001219:Aspartate Aminotransferases; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D004796:Clinical Enzyme Tests; D004833:Epilepsy, Temporal Lobe; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008111:Liver Function Tests; D011237:Predictive Value of Tests; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "9423309", "other_id": null, "pages": "471-3", "pmc": null, "pmid": "25907173", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of lacosamide-induced hepatotoxicity.", "title_normalized": "a case of lacosamide induced hepatotoxicity" }

[ { "companynumb": "KR-UCBSA-2015015059", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022253", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TIANEPTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZONISAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TIANEPTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SUNWOO JS, BYUN JI, LEE SK. A CASE OF LACOSAMIDE-INDUCED HEPATOTOXICITY. INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS. 2015", "literaturereference_normalized": "a case of lacosamide induced hepatotoxicity", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20150514", "receivedate": "20150514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11111559, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "Objectives: To report an oxcarbazepine (OXC)-induced cutaneous reaction in a female of Mexican ancestry. Case Summary: A 60-year-old female of Mexican ancestry presented to clinic with a diffuse morbilliform rash, with erythema and eruptions of papules/pustules concentrated on her neck and torso. The rash appeared 1 week following the initiation of OXC for trigeminal neuralgia. Initially, the correlation between the reaction and initiation of OXC was not recognized by the provider. OXC was continued for a total of 4 weeks and several medical encounters transpired in the interim. Supportive therapy, in the form of oral antihistamines and oral/topical corticosteroids, failed to resolve the rash. A clinical pharmacist prompted the discontinuation of OXC due to suspicion that it incited the adverse reaction. Oral corticosteroid therapy was initiated and tapered over 2 weeks, with rash dissipation occurring in 1 month. Discussion: The association of OXC with the cutaneous eruption was classified as \"probable\" based on the Naranjo Scale. While financial resources were not available to perform genetic testing, it may be possible that the genetic status of this patient lent itself to greater potential for cutaneous reactions with OXC. Further research is needed to determine whether pharmacogenetic variables affiliated with pre-Columbian lineage may predispose individuals to specific adverse drug reactions. Conclusion: As regional genotypes disperse globally, it is imperative that clinicians are cognizant of risks regarding genetically implicated adverse drug reactions. While information is limited for certain ethnicities, it is essential that providers diligently monitor all populations for reactions characteristic to specific medications.", "affiliations": "University of Texas at Tyler, Tyler, TX, USA.;University of Texas at Tyler, Tyler, TX, USA.", "authors": "Reinert|Justin P|JP|;Cook|Elizabeth A|EA|https://orcid.org/0000-0002-3496-9587", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/8755122519850477", "fulltext": null, "fulltext_license": null, "issn_linking": "1549-4810", "issue": "35(4)", "journal": "The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians", "keywords": "adverse drug reactions; anticonvulsants; medication safety; neurology; pharmacogenetics and pharmacogenomics", "medline_ta": "J Pharm Technol", "mesh_terms": null, "nlm_unique_id": "8504643", "other_id": null, "pages": "179-183", "pmc": null, "pmid": "34752516", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": "25495410;27651712;18821094;17386054;22429379;10718894;14791600;21449936;21428769;7249508;23882307;25933949;18490142;1379159;22528618;9276112;17362215;22424655;19153346;23108810;1430701;24926019", "title": "Oxcarbazepine-Induced Cutaneous Reaction in a Female of Mexican Ancestry.", "title_normalized": "oxcarbazepine induced cutaneous reaction in a female of mexican ancestry" }

[ { "companynumb": "PHHY2019US166036", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021014", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TRIGEMINAL NEURALGIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERCHOLESTEROLAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash morbilliform", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash papular", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "22.0", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "REINERT JP, COOK EA. OXCARBAZEPINE-INDUCED CUTANEOUS REACTION IN A FEMALE OF MEXICAN ANCESTRY. JOURNAL OF PHARMACY TECHNOLOGY. 2019?35(4):179-83", "literaturereference_normalized": "oxcarbazepine induced cutaneous reaction in a female of mexican ancestry", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190905", "receivedate": "20190723", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16619152, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "Acute respiratory distress syndrome, characterized by the Berlin criteria, is associated with a high mortality rate. Its treatment includes addressing the underlying etiology, general supportive measures, and achievement of effective oxygenation. New key data indicates that in a subset of patients, noninvasive ventilation techniques can be a therapeutic and equivalent alternative to traditional invasive ventilation. We present a rare case of ARDS triggered by nasal bupropion inhalation and effectively treated with noninvasive positive pressure ventilation resulting in complete resolution.", "affiliations": "Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.;Department of Pulmonary/Critical Care, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA.", "authors": "Al-Saiegh|Yousif|Y|https://orcid.org/0000-0003-4579-8610;Spears|Jenna|J|https://orcid.org/0000-0003-0182-7774;De Klerk|Pieter S|PS|;Hitchings|Joshua|J|;Lee|Christopher|C|https://orcid.org/0000-0003-3851-9206;Mahr|Tamara|T|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2020/5107456", "fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420 2090-6439 Hindawi \n\n10.1155/2020/5107456\nCase Report\nA Rare Case of ARDS Caused by Bupropion Inhalation and Treated with Noninvasive Ventilation\nhttps://orcid.org/0000-0003-4579-8610Al-Saiegh Yousif [email protected]\n1\n https://orcid.org/0000-0003-0182-7774Spears Jenna \n1\n De Klerk Pieter S. \n1\n Hitchings Joshua \n1\n https://orcid.org/0000-0003-3851-9206Lee Christopher \n1\n Mahr Tamara \n2\n \n1Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA\n\n2Department of Pulmonary/Critical Care, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia PA, USA\nAcademic Editor: Mabrouk Bahloul\n\n\n2020 \n28 5 2020 \n2020 510745629 1 2020 23 3 2020 Copyright © 2020 Yousif Al-Saiegh et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Acute respiratory distress syndrome, characterized by the Berlin criteria, is associated with a high mortality rate. Its treatment includes addressing the underlying etiology, general supportive measures, and achievement of effective oxygenation. New key data indicates that in a subset of patients, noninvasive ventilation techniques can be a therapeutic and equivalent alternative to traditional invasive ventilation. We present a rare case of ARDS triggered by nasal bupropion inhalation and effectively treated with noninvasive positive pressure ventilation resulting in complete resolution.\n==== Body\n1. Introduction\nAcute respiratory distress syndrome (ARDS) incorporates a cluster of clinical features including shortness of breath and tachypnea and is defined by the Berlin criteria as having an acute onset with the development of hypoxemia and bilateral pulmonary opacities on radiographic imaging [1]. There are many causes of ARDS; however, most often, it is triggered by infections, blood transfusions, direct lung injury, and toxins [2]. Treatment includes removal of the inciting cause, supportive therapy, and the attainment of sufficient blood oxygenation. Adequate oxygenation in ARDS is often achieved by endotracheal intubation and mechanical ventilation. Noninvasive positive pressure ventilation (NIPPV) has been less frequently indicated as an alternative form of adequate oxygenation. Typically, its use is focused and intended on preventing complications that are associated with invasive ventilation such as barotrauma, vocal cord injury, and ventilator-associated pneumonia [3].\n\nBupropion is an atypical oral antidepressant medication commonly used to treat depression, tobacco dependence, obesity, and hypoactive sexual disorder. Its mechanism of action involves the inhibition and reuptake of norepinephrine and dopamine which can induce a state of euphoria. Because of these effects, bupropion has been reported to be abused recreationally [4, 5]. We describe a case of ARDS induced by bupropion inhalation that was treated with NIPPV.\n\n2. Case Presentation\nA 30-year-old male with a past medical history significant for polysubstance abuse presented to the emergency department (ED) two hours after ingesting 90 mg of oxycodone and 30 mg of diazepam along with intranasal bupropion. On arrival, he complained of extreme fatigue, respiratory distress, and confusion.\n\nIn the ED, he was noted to be lethargic and short of breath. Initial vital signs revealed heart rate of 104 beats per minute, respiratory rate of 35 per minute, and O2 saturation of 75% on room air. Respiratory exam revealed diffuse bilateral coarse breath sounds on inspiration and expiration. His laboratory results were notable for a leukocytosis of 14.1 K, creatinine of 1.25 g/dl, lactate of 4.1, and an elevated procalcitonin level. Venous blood gas analysis showed a pH of 7.18 with a pCO2 of 51 mmHg. Chest X-ray (CXR) demonstrated diffuse bilateral alveolar infiltrates (Figure 1(a)). Computed tomography (CT) of the chest showed diffuse bilateral airspace disease characterized by groundglass and consolidative opacities with relative peripheral lung sparing and perihilar predominance (Figure 2). He received naloxone with mild improvement in mental status and was initiated on Bilevel Positive Airway Pressure (BiPAP) with an inspiratory positive airway pressure (IPAP) of 15 cm H2O, expiratory positive airway pressure (EPAP) of 5 cm H2O with 40% fraction of inspired oxygen (FiO2). Empiric broad spectrum antibiotics including vancomycin, cefepime, and metronidazole were initiated along with intravenous methylprednisolone 40 mg every 12 hours.\n\nInitially while on BIPAP, he remained tachypneic and tachycardic. His respiratory rate improved over the following 6 hours. He was gradually weaned off BiPAP to nasal cannula oxygen over the course of 36 hours while receiving ongoing corticosteroid and antibiotic therapy.\n\nRepeat CXR on hospital day #6 showed markedly improved bilateral airspace opacities (Figure 1(b)). After 6 days, he was discharged in stable condition without requiring supplemental oxygen.\n\n3. Discussion\nARDS is associated with a high mortality that has declined from over 50% to 30% over the last four decades [6, 7]. This is primarily due to implementation of lung-protective ventilation protocols and intensified research after formation of the National Heart, Lung, and Blood Institute (NHLBI) ARDS network [8, 9]. This case highlights a mild manifestation of ARDS as a result of bupropion inhalation, an exceedingly rare etiology.\n\nThe Food and Drug Administration (FDA) classifies bupropion as a psychiatric medication with low abuse potential [10]. However, several case reports and studies have indicated increasing recreational use of bupropion mostly intravenously or intranasally [11–13]. Lewis et al. conducted a review on bupropion inhalation in a total of 67 patients. Seizures were noted as a common adverse effect occurring in 30% of patients. Acute lung toxicity was not reported as a complication [14]. We were not able to find a second reported case of bupropion-inhalation-induced ARDS.\n\nEndotracheal intubation and mechanical ventilation are mostly required to ensure adequate oxygenation, but this was avoided in this patient as we maintained adequate oxygenation with BiPAP alone. NIPPV is advantageous in such patients as it does not expose them to the potential complications of invasive ventilation and may shorten their hospital length of stay [3]. There is, however, an ongoing debate concerning the most effective mode of NIPPV [15, 16]. Recent studies show that noninvasive ventilation can be used in mild cases of ARDS with acute nonhypercapnic hypoxemic respiratory failure [17]. In these cases, BiPAP via facemask is the most commonly used strategy [18]. Another approach with high-flow nasal cannula was shown to have a similar degree of treatment failure and incidence of subsequent intubation as BiPAP. High-flow nasal cannula, however, was associated with decreased 90-day mortality as compared to BiPAP [19]. A randomized, single-center trial by Pohlman et al. showed that delivering noninvasive ventilation via helmet instead of by facemask was associated with a significant reduction in intubations. There was also a decrease in intensive care unit length of stay and mortality at 90 days [20]. However, a subset analysis of the observational “LUNG-SAFE” study for patients with severe ARDS (defined as a PaO2/FiO2 ratio below 150 mmHg) showed increased mortality with noninvasive ventilation [21].\n\nPer our review, data on the use of noninvasive ventilation in the management of ARDS remains inconclusive and conflicting. NIPPV may decrease the incidence of ventilator-associated complications; however, given that its efficacy is not well established, patients with ARDS should still be treated in a critical care setting for close monitoring with invasive ventilation available on standby.\n\n4. Conclusion\nAdvances in the treatment of the underlying etiologies and improvement in mechanical ventilation strategies have led to a decrease in the overall mortality associated with ARDS. Despite these developments, it remains a diagnosis with an exceedingly high mortality. New emerging data indicates that NIPPV can be a beneficial and equivalent approach for a subset of patients with ARDS, although the optimal type of noninvasive ventilation and patient group that would benefit most is yet to be determined.\n\nConflicts of Interest\nAll authors declare no conflict of interest.\n\nFigure 1 (a) Single-view anterior-posterior chest X-ray on day #1 showed diffuse bilateral lung opacities. (b) Repeat single-view anterior-posterior chest X-ray on day #6 showed decreased airspace opacities.\n\nFigure 2 Contrast-enhanced computed tomography of the chest on day #2 shows diffuse bilateral airspace disease characterized by groundglass and consolidative opacities, with relative peripheral sparing and perihilar predominance. No pleural effusions or pneumothorax.\n==== Refs\n1 The ARDS Definition Task Force Acute respiratory distress syndrome: the Berlin definition JAMA 2012 307 2526 2533 10.1001/jama.2012.5669 2-s2.0-84862490519 22797452 \n2 Fan E. Brodie D. Slutsky A. S. Acute respiratory distress syndrome: advances in diagnosis and treatment JAMA 2018 319 7 698 710 10.1001/jama.2017.21907 2-s2.0-85042281861 29466596 \n3 Taha A. Larumbe-Zabala E. Abugroun A. Mohammedzein A. Naguib M. T. Patel M. Outcomes of noninvasive positive pressure ventilation in acute respiratory distress syndrome and their predictors: a national cohort Critical Care Research and Practice 2019 2019 8 8106145 10.1155/2019/8106145 2-s2.0-85072983506 31641538 \n4 Arias H. R. Is the inhibition of nicotinic acetylcholine receptors by bupropion involved in its clinical actions? The International Journal of Biochemistry & Cell Biology 2009 41 11 2098 2108 10.1016/j.biocel.2009.05.015 2-s2.0-70349267544 19497387 \n5 Langguth B. Hajak G. Landgrebe M. Unglaub W. Abuse potential of bupropion nasal insufflation: a case report Journal of Clinical Psychopharmacology 2009 29 6 618 619 10.1097/JCP.0b013e3181c09475 2-s2.0-72949087811 19910738 \n6 Milberg J. A. Davis D. R. Steinberg K. P. Hudson L. D. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993 JAMA 1995 273 4 306 309 10.1001/jama.1995.03520280052039 2-s2.0-0028798336 7815658 \n7 Ashbaugh D. G. Bigelow D. B. Petty T. L. Levine B. E. Acute respiratory distress in adults The Lancet 1967 2 7511 319 323 10.1016/s0140-6736(67)90168-7 4143721 \n8 Amato M. B. P. Barbas C. S. V. Medeiros D. M. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome The New England Journal of Medicine 1998 338 6 347 354 10.1056/NEJM199802053380602 2-s2.0-0032484956 9449727 \n9 Thompson B. T. Bernard G. R. ARDS network (NHLBI) studies: successes and challenges in ARDS clinical research Critical Care Clinics 2011 27 3 459 468 10.1016/j.ccc.2011.05.011 2-s2.0-79960143563 21742211 \n10 Substance abuse treatment for persons with HIV/AIDS 2000 Rockville Substance Abuse and Mental Health Services Administration (US) \n11 Stall N. Godwin J. Juurlink D. Bupropion abuse and overdose CMAJ 2014 186 13 p. 1015 10.1503/cmaj.131534 2-s2.0-84921626320 24778361 \n12 Stassinos G. L. Klein-Schwartz W. Bupropion \"abuse\" reported to US poison centers Journal of Addiction Medicine 2016 10 5 357 362 10.1097/ADM.0000000000000249 2-s2.0-84996508810 27504927 \n13 Starr P. Klein-Schwartz W. Spiller H. Kern P. Ekleberry S. E. Kunkel S. Incidence and onset of delayed seizures after overdoses of extended-release bupropion The American Journal of Emergency Medicine 2009 27 8 911 915 10.1016/j.ajem.2008.07.004 2-s2.0-70349185366 19857406 \n14 Lewis J. C. Sutter M. E. Albertson T. E. Owen K. P. Ford J. B. An 11-year review of bupropion insufflation exposures in adults reported to the California Poison Control System Clinical Toxicology 2014 52 9 969 972 10.3109/15563650.2014.969372 2-s2.0-84910091245 25308323 \n15 Messika J. Ben Ahmed K. Gaudry S. Use of high-flow nasal cannula oxygen therapy in subjects with ARDS: a 1-year observational study Respiratory Care 2015 60 2 162 169 10.4187/respcare.03423 2-s2.0-84930512185 25371400 \n16 Ou X. Hua Y. Liu J. Gong C. Zhao W. Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials CMAJ 2017 189 7 E260 E267 10.1503/cmaj.160570 2-s2.0-85014057578 28246239 \n17 Zhan Q. Sun B. Liang L. Early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial Critical Care Medicine 2012 40 2 455 460 10.1097/CCM.0b013e318232d75e 2-s2.0-84856216479 22020236 \n18 Kredel M. Bierbaum D. Lotz C. Kustermann J. Roewer N. Muellenbach R. M. Therapy of acute respiratory distress syndrome : survey of German ARDS centers and scientific evidence Anaesthesist 2015 64 4 277 285 10.1007/s00101-015-0010-1 2-s2.0-84937763236 25824000 \n19 Frat J. P. Thille A. W. Mercat A. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure The New England Journal of Medicine 2015 372 23 2185 2196 10.1056/NEJMoa1503326 2-s2.0-84930535780 25981908 \n20 Patel B. K. Wolfe K. S. Pohlman A. S. Hall J. B. Kress J. P. Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial JAMA 2016 315 22 2435 2441 10.1001/jama.2016.6338 2-s2.0-84974802607 27179847 \n21 Bellani G. Laffey J. G. Pham T. Noninvasive ventilation of patients with acute respiratory distress syndrome. Insights from the LUNG SAFE study American Journal of Respiratory and Critical Care Medicine 2017 195 1 67 77 10.1164/rccm.201606-1306OC 2-s2.0-85008690467 27753501\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2020()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "5107456", "pmc": null, "pmid": "32550027", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "24778361;4143721;22020236;31641538;27179847;25981908;27504927;21742211;29466596;19910738;25371400;19497387;9449727;25824000;28246239;7815658;25308323;27753501;19857406;22797452", "title": "A Rare Case of ARDS Caused by Bupropion Inhalation and Treated with Noninvasive Ventilation.", "title_normalized": "a rare case of ards caused by bupropion inhalation and treated with noninvasive ventilation" }

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{ "abstract": "Managing migraines complicated with medication overuse headaches and opioid-induced hyperalgesia can be challenging, especially within the geriatric and chronic pain population. A 65-year-old woman with a degenerative spine condition and chronic migraine headaches, along with other comorbidities, was admitted to the geriatric psychiatry unit for extreme mood swings and paranoia. Prior to admission, she had been taking extended-release morphine sulfate twice daily for more than a month and was unable to determine triggers to her frequent migraine headaches. She had a history of medication overuse and severe migraine episodes within 4 weeks prior to admission. This case report reviews the challenges of treating a geriatric patient with probable chronic migraines in addition to other pain conditions and comorbidities.", "affiliations": "Doctor of Pharmacy, University of Maryland School of Pharmacy, Baltimore, Maryland.;(Corresponding author) Clinical Pharmacist, Sheppard Pratt Health System, Towson, Maryland, [email protected].", "authors": "Bach|Linda Lu|LL|;Goga|Joshana|J|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.9740/mhc.2016.05.154", "fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2016.05.154mhcl-06-02-05Customer: MHC-D-14-00048R3Open SubmissionsManagement of migraine headaches in a chronic pain patient: A case report Bach Linda Lu PharmD1Goga Joshana PharmD, BCPP2\n1 Doctor of Pharmacy, University of Maryland School of Pharmacy, Baltimore, Maryland\n\n2 (Corresponding author) Clinical Pharmacist, Sheppard Pratt Health System, Towson, Maryland, [email protected]\n6 2016 6 5 2016 6 3 154 158 © 2016 CPNP.2016The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Managing migraines complicated with medication overuse headaches and opioid-induced hyperalgesia can be challenging, especially within the geriatric and chronic pain population. A 65-year-old woman with a degenerative spine condition and chronic migraine headaches, along with other comorbidities, was admitted to the geriatric psychiatry unit for extreme mood swings and paranoia. Prior to admission, she had been taking extended-release morphine sulfate twice daily for more than a month and was unable to determine triggers to her frequent migraine headaches. She had a history of medication overuse and severe migraine episodes within 4 weeks prior to admission. This case report reviews the challenges of treating a geriatric patient with probable chronic migraines in addition to other pain conditions and comorbidities.\n\nKeywords\nmigrainemedication overuse headacheopioid-induced hyperalgesiachronic paingeriatricopioid\n==== Body\nIntroduction\nMigraines are a type of headache associated with nausea, vomiting, and/or sensitivity to light. The headache can be potentiated by abnormal brain activity triggered by caffeine withdrawal, changes in sleep patterns, loud noises, bright lights, various foods, stress, or anxiety. Currently, there is no cure for migraine headaches. The goal of treatment is to manage symptoms and prevent recurrence.1 Guidelines exist for preventing recurring migraines and treating acute attacks, but patients with coexisting chronic pain may pose additional challenges to these treatments. These patients are at risk for medication overuse headaches (MOHs) and opioid-induced hyperalgesia (OIH) due to regular intake of acute or chronic analgesics.\n\nWhen managing migraines, treatment approach is similar for chronic (≥15 migraines per month for more than 3 months on ≥8 days per month) and episodic migraines (<15 migraines per month); both include prophylactic therapy and acute therapy.2 The American Academy of Neurology guidelines for migraine recurrence prevention lists several medications shown to be effective in migraine prevention3:\n\nAntiepileptic drugs: topiramate and valproic acid and derivatives\n\nBeta-blockers: metoprolol, propranolol, and timolol\n\nTriptans: for short-term menstrually associated migraine prevention\n\nIn clinical practice, first-line prophylactic medications for chronic migraine include the following4:\n\nPropanolol\n\nAmitriptyline\n\nTopiramate\n\nValproic acid and derivatives (second line in women due to teratogenicity)\n\nIn 2 randomized, double-blinded, placebo-controlled trials, topiramate was found to be effective and well-tolerated in patients with chronic migraine with or without presence of medication overuse.5,6 Botulinum toxin injections may also be an option in reducing migraine attacks if they occur more than 15 days a month.1 OnabotulinumtoxinA has been approved by the US Food and Drug Administration to treat chronic migraine.\n\nFor acute treatment options, first-line therapies include the following7:\n\nAcetaminophen/aspirin/caffeine combination analgesic\n\nNonsteroidal anti-inflammatory drugs (eg, ibuprofen and naproxen)\n\nTriptans (eg, sumatriptan)\n\nTriptan/nonsteroidal anti-inflammatory drugs combination analgesic (eg, sumatriptan/naproxen)\n\nAccording to the International Headache Society, MOH is characterized by (1) a headache present for ≥15 days per month with a preexisting headache disorder, (2) regular overuse for more than 3 months of one or more drugs taken for acute and/or symptomatic treatment of headache, and (3) a headache developed or markedly worsened during medication overuse (ie, ≥15 days per month of simple analgesics and combination acute medications or ≥10 days per month of triptans, ergotamines, opioids, and/or combination analgesics).2,8 Risk factors for MOH include previous primary headaches (eg, migraine and tension headaches) in addition to a history of substance abuse, regular use of tranquilizers, or an increased score on the Hospital Anxiety and Depression Scale.8 Depression and anxiety are also common coexisting conditions in patients with MOH, which may be related to the frequency of headaches these patients experience. Chronic pain medication therapies, especially with opioids, have the potential to trigger MOH as well as induce migraines and other types of headaches.\n\nFor people receiving long-term opioid therapy, pain management can be limited not only by opioid tolerance but also by OIH, which is characterized by increased pain sensitization as a result of increased or long-term opioid exposure.9,10 There are multiple theories on the cause of OIH, but the most studied mechanism is the increased activation of N-methyl-D-aspartate (NMDA) receptors by opioids, which can cause more pain impulse transmissions and affect the amount of pain sensitivity in both acute and chronic pain states.11,12 According to a prospective study, some patients on oral morphine therapy experienced both analgesic tolerance and hyperalgesia within 1 month of initiating therapy.10 In addition, the occurrence of OIH may be due to accumulation of toxic opioid metabolites, such as morphine-3-glucuronide, which may act as NMDA agonists and lead to other opioid hyperexcitability effects, such as delirium and seizures.11,13,14 Clinicians should suspect OIH if treatment effect appears to decline in absence of disease progression or if there are unexplained pain reports unrelated to the site of injury.15 Treatments for OIH include the following:\n\nReducing opioid exposure by reducing the dose or removing it from therapy11,16,17\n\nOpioid rotation or switching to a different opioid11,17,18\n\nAdding an NMDA receptor antagonist (eg, methadone, cyclooxygenase-2 inhibitors)11,17,19\n\nAdding alpha-2 receptor agonists (eg, clonidine)17\n\nManaging migraines in patients complicated with MOH and OIH can be challenging, especially in the geriatric population, because the prevalence of persistent pain increases with age and most geriatric patients have significant pain problems that are not adequately relieved.20 Opioids are the “gold standard” for therapeutic management of chronic pain, and with many of the elderly being treated for chronic pain, the geriatric population is at higher risk of OIH.9 A study of 2 health plans found that from 1997 to 2005 the total percentage increase in prevalence of long-term opioid use ranged from 61% to 135%; women aged 65 years or older had the highest prevalence in 2005.21 In the Group Health cooperative study from 2005, 44.1% of those aged 65 years or older were on long-term schedule II opioid treatment.21 Also, from 1998 to 2006, regular opioid use increased with age, and the prevalence of regular opioid use in those aged 70 years or older was 3.4% by 2006.22 Arthritis and back pain were the most common chronic conditions found among regular users of opioids, and most of these users had more than one pain condition that needed treatment.23 The following case report reviews the challenges of treating a geriatric patient with probable chronic migraine in addition to other patient-related variables.\n\nCase Description\nThe patient, a 65-year-old woman, was admitted to the geriatric psychiatry inpatient unit due to depression, severe anxiety, paranoia, delirium, and extreme mood swings. She reported poor sleep and poor appetite and had expressed problems with concentration. She also reported painful migraines and had been admitted to a community hospital for a migraine episode prior to admission. When asked about headache triggers, the patient noticed that caffeine, particularly coffee, and loud voices were possible triggers but otherwise had not noticed any other trigger patterns for her chronic migraines. At least 2 reports of migraine headaches coinciding with overmedication were found within the 2 weeks prior to admission in external records (Table 1). Her relevant past medical history included depression, frequent migraines, arthritis, and chronic neck and spine pain from her degenerative spine condition. Her family history included migraines in her maternal grandmother, and her social history included substance abuse with opioids.\n\nTABLE 1: Pharmacy medication records 3 months prior to admission\n\nThe patient reported being compliant with medications, though she stated that she had decreased her topiramate prior to admission due to her concern about weight loss. The patient had been seeing a psychotherapist and psychiatrist but failed to follow up after relocating and facing financial burden. The patient last saw her psychiatrist about a year prior to admission, and all her psychiatric medications were being prescribed by her neurologist. She also had a pain specialist who at first prescribed extended-release morphine sulfate 30 mg twice daily for her chronic spine pain but then switched her to oxycodone 5 mg 5 times daily prior to admission. All medications dispensed 3 months prior to admission came from 2 pharmacies.\n\nAccording to the patient, her current life stressors included finances, adjusting to her new home, and lack of sleep. During the first interview, the patient reported that she was addicted to morphine and was withdrawing from it. She also reported not abusing her medications and only following the instructions on the medication labels. Her husband and primary care physician did not believe she was abusing her medications.\n\nFor migraine treatment, the patient reported that she had tried beta blockers in the past and those did not work for her. The patient also reported that her divalproex delayed release was discontinued and that acetaminophen “spiked” her liver enzymes. Additionally, the patient mentioned that her neurologist said she was a candidate for botulinum toxin injection and before admission had scheduled her to have a treatment within the next couple of months. The patient admitted to consuming caffeinated sodas around the clock prior to admission.\n\nDuring admission, the patient's problem list included bipolar II disorder, anxiety, insomnia, migraines, chronic spinal pain, neuropathic pain, arthritis, hypertension, hypothyroidism, and gastroesophageal reflux disease. Bipolar II disorder was a new diagnosis during this admission, and relevant medications were added or increased in dose to minimize side effects and optimize overall therapy. Reports were unclear as to whether the patient's frequent migraines existed prior to medication overuse or if medication overuse caused the frequent migraines. Regardless, the patient was converted to oxycodone, topiramate was titrated to 100 mg daily for migraine prophylaxis, and the patient was counseled to reduce caffeine consumption. Also, methylphenidate was originally not included in overall therapy due to risk of worsening migraines but was eventually added at a low dose to improve patient affect and energy. Neuropathic pain was another new diagnosis during admission, and thus gabapentin was added into overall therapy. Toward the time of discharge, the patient reported worsening arthritis that affected her sleep, and naproxen was prescribed as needed to address the pain and improve sleep. The patient's overall pain ranged between 3 and 8 out of 10; however, most scores hovered around 5 of 10 with 10 being the worst pain imaginable.\n\nHer vital signs were all within normal limits and renal function remained normal. The medications prescribed upon discharge after 3 weeks of admission are shown in Table 2.\n\nTABLE 2: Discharge medications\n\nThe patient was referred for follow-up with her neurologist and a new pain specialist upon discharge.\n\nDiscussion\nIn controlling migraine recurrence, this patient's modifiable risk factors included depression, anxiety, stress triggers, previous chronic caffeine exposure, medication overuse, and chronic pain. Previous longitudinal studies support a bidirectional relationship between depression and migraines.24 Also, the effects of depression and anxiety can worsen migraine symptoms and frequency. Stress can trigger headaches, and in this case the patient's financial and living situation, lack of sleep, and other stressors may have contributed to her chronic migraines. The patient admitted to consuming caffeinated sodas around the clock prior to admission, which can lead to withdrawal from chronic consumption and trigger migraine headaches. Additionally, medication overuse with barbiturates or opiates can cause rebound headache and OIH, and in this patient's case, she had been taking extended-release morphine sulfate twice daily for more than a month prior to admission. Finally, the patient continued to have chronic pain from her degenerative spine condition, which was not adequately managed and potentially exaggerated from OIH. Managing these risk factors would improve this patient's frequent migraines.\n\nDuring admission, the treatment focused on managing the patient's psychiatric conditions, her overall pain, and her frequent migraines. Because morphine sulfate is known to metabolize into codeine and morphine-3-glucuronide and the patient was delirious prior to admission while being on morphine sulfate, she was switched from extended-release morphine sulfate to oxycodone to reduce probable MOH, opioid toxicity, and OIH.25 Since then, the patient has had reduced symptoms of delirium, and her overall pain has remained relatively stable around 5 out of 10. With the new onset of neuropathic pain, gabapentin was also added and adequately managed this pain without worsening other therapies. Finally, naproxen was given as needed to relieve worsening arthritic pain, and it adequately managed her arthritis without inducing additional headaches. Because the patient still had unrelieved moderate-level pain in her neck and back, the patient was told to follow up with her pain specialist and neurologist to manage her pain and frequent migraines.\n\nWhile the patient was being treated for anxiety and depression, her migraines were managed according to current migraine guidelines. At least 2 randomized placebo-controlled trials support the use of topiramate for chronic migraine prophylaxis compared with the lower-quality evidence for use of valproic acid and derivatives.4-6 The patient also reported having been discontinued on divalproex and taking topiramate before admission. After multiple interviews, and considering the patient's overall condition and medication history, the patient agreed to take topiramate at bedtime for migraine recurrence prevention and sumatriptan for acute migraine attacks. She was also advised to record any migraine triggers so that she could identify patterns and try to avoid them. Finally, the patient was counseled on how and why she takes her medications and the risks and side effects involved with each one, especially with oxycodone and topiramate as she has a history of medication overuse and self-decreased dosing. Since then, the patient has worked on identifying more migraine triggers and appeared to have better affect as well as reduced severity and frequency of migraines.\n\nEven though methylphenidate can potentially worsen migraines, the patient reported improved concentration and productivity at a low dose without worsening migraines. The patient also achieved her original weight as overall mood, affect, and pain improved. Although the patient was improving in most aspects of therapy, however, her migraines and overall pain were not adequately relieved. In conclusion, this case report discusses the challenges of managing migraines when chronic pain management and other conditions are involved. 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Available from: http://www.micromedexsolutions.com.proxy-hs.researchport.umd.edu/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/FFB3C8/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/14FFE9/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.DisplayDrugdexDocument?docId=0516&contentSetId=31&title= Morphine+Sulfate&servicesTitle=Morphine+Sulfate&topicId= pharmacokineticsSection .\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2168-9709", "issue": "6(3)", "journal": "The mental health clinician", "keywords": "chronic pain; geriatric; medication overuse headache; migraine; opioid; opioid-induced hyperalgesia", "medline_ta": "Ment Health Clin", "mesh_terms": null, "nlm_unique_id": "101728585", "other_id": null, "pages": "154-158", "pmc": null, "pmid": "29955463", "pubdate": "2016-06", "publication_types": "D002363:Case Reports", "references": "18619768;25061336;17441971;17300356;16414554;18574358;16082916;18816332;20724688;21770930;21412369;24382350;21302868;18342447;23771276;10567729;18686750;22584979;17040330;22529202;21603375", "title": "Management of migraine headaches in a chronic pain patient: A case report.", "title_normalized": "management of migraine headaches in a chronic pain patient a case report" }

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PRN", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "25 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "MIGRAINE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paranoia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mood swings", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperaesthesia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuralgia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Delirium", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Migraine", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Medication overuse headache", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Bipolar II disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Disturbance in attention", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BACH LL, GOGA J. MANAGEMENT OF MIGRAINE HEADACHES IN A CHRONIC PAIN PATIENT: A CASE REPORT. MENT HEALTH CLIN. 2016?6(3):154?8", "literaturereference_normalized": "management of migraine headaches in a chronic pain patient a case report", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180706", "receivedate": "20180706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15117384, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]

{ "abstract": "Emergency physicians (EPs) can use bedside ultrasound to diagnosis of intraabdominal free fluid in a variety of clinical scenarios.The purpose of this study is to review the sonographic appearance of intraabdominal free fluid and incidence of spontaneous splenic rupture. An EP used bedside ultrasound to diagnose spontaneous splenic rupture in a patient who had received tissue plasminogen activator for suspected acute ischemic stroke. Bedside ultrasound by a physician trained in basic ultrasound and the focused assessment with sonography for trauma can diagnose intraabdominal free fluid, facilitating appropriate and more rapid consultation, advanced imaging, and treatment.", "affiliations": "Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].;Brigham and Women's Hospital, Boston, MA. Electronic address: [email protected].;Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].;Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].;Massachusetts General Hospital, Boston, MA. Electronic address: [email protected].", "authors": "Genthon|Alissa|A|;Frasure|Sarah|S|;Kinnaman|Karen|K|;Huang|Calvin|C|;Noble|Vicki|V|", "chemical_list": "D010959:Tissue Plasminogen Activator", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "32(12)", "journal": "The American journal of emergency medicine", "keywords": null, "medline_ta": "Am J Emerg Med", "mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D006470:Hemorrhage; D006801:Humans; D019095:Point-of-Care Systems; D013154:Spleen; D013158:Splenic Diseases; D020521:Stroke; D010959:Tissue Plasminogen Activator; D014463:Ultrasonography", "nlm_unique_id": "8309942", "other_id": null, "pages": "1553.e1-2", "pmc": null, "pmid": "25303848", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration.", "title_normalized": "bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration" }

[ { "companynumb": "US-ROCHE-1521220", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103172", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC STROKE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTILYSE" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperhidrosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Splenic haemorrhage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GENTHON A, FRASURE S, KINNAMAN K, HUANG C, AND NOBLE V. BEDSIDE ULTRASOUND DIAGNOSIS OF A SPONTANEOUS SPLENIC HEMORRHAGE AFTER TISSUE PLASMINOGEN ACTIVATOR ADMINISTRATION. AMERICAN JOURNAL OF EMERGENCY MEDICINE 2014 DEC 01;32 (12):1553.E1-1553.E2.", "literaturereference_normalized": "bedside ultrasound diagnosis of a spontaneous splenic hemorrhage after tissue plasminogen activator administration", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150121", "receivedate": "20150116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10715234, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]